Prinicipal Investigator

Scientific interest within the context of the graduate college:

Our lab is interested in analyzing immune cells in the tissue context, using state-of-the art, functional intravital microscopy and histocytometry approaches1,2,3. In addition to reacting to stimuli from hematopoietic and non-hematopoietic cells, for example via direct cell-cell contacts or via soluble mediators, immune cells are exposed to a variety of other stimuli present in the tissue, among them mechanical cues. The significance of those stimuli for immune cells has not been explored in detail. Recently, a role for the mechanosensor Piezo1 in shaping myeloid cell activation has been identified4. Here, we aim to understand how mechanical cues in barrier tissues affect the function of myeloid cells. We will focus the lamina propria of the intestine, a tissue that in the healthy organism is constantly subjected to contractions (peristalsis). We hypothesize that this mechanical stimulation impacts on the phenotype of macrophages in the lamina propria. As alterations in peristalsis appear in certain situations, such as parasitic infections, we aim to test to what extent mechanosensing in macrophages affects their function under those conditions.

Project description:

To monitor mechanosensing in vivo, we aim to use a reporter system, which allows for the detection of Ca2+ flux, induced by the mechanosensor Piezo1, in intestinal macrophages by intravital microscopy5. The objectives for this project are:

Aim 1: Determine the effect of mechanical stimuli on the phenotype of macrophages in vitro. Myeloid cells will be cultured and various, defined mechanical stimuli will be applied in a specialized chamber. The phenotypes of the cells will be compared by flow cytometry.

Aim 2: Define the role of the Ca2+ channel Piezo1 in myeloid mechanosensing and establish a reporter system for the quantification of Piezo1-mediated Ca2+ flux in vitro and in vivo. The impact of Piezo1 stimulation on cytoplasmic Ca2+ concentration will be assessed using specific inhibitors/activators in vitro. To quantify Piezo1-induced Ca2+ flux in the cytoplasm in vivo, we plan to use mice carrying a genetically encoded cytoplasmic calcium sensor in macrophages. We will relate the sensor signals to mechanical stimuli in vitro. Subsequently, we aim to employ this system to locate and quantify mechanically induced Ca2+ flux in myeloid cells by intravital FRET-FLIM microscopy6, and correlate this signal totissue dynamics, to map the pressure conditions in vivo.

Aim 3: Determine to what extent Piezo1-mediated mechanosensing in myeloid cells of the lamina propria contributes to the intestinal immune response in vivo. The phenotype of intestinal macrophages will be compared by flow cytometry and multiplexed histology in mice with a deficiency of Piezo1 in myeloid cells to wildtype mice. Initial analyses will be performed under homeostatic conditions. Subsequently, we will challenge the mice by infecting them with intestinal parasites, which are known to mechanically impact on the tissue, either by attaching to the intestinal wall, or by inducing altered gut peristalsis.

Application details

References

  1. Pascual-Reguant A, Kohler R, Mothes R, Bauherr S, Uecker R, Holzwarth K, Kotsch K, Seidl M, Philipsen L, Müller W, Hernández D, Romagnani C, Niesner R, Hauser AE. Phenotypic and spatial characteristics of human Innate Lymphoid Cells revealed by highly multiplexed histology. Nat Commun. 2021. Accepted for publication.
  2. Stefanowski J, Lang A, Rauch A, Aulich L, Kohler M, Fiedler AF, Buttgereit F, Schmidt-Bleek K, Duda GN, Gaber T, Niesner RA, Hauser AW. Spatial Distribution of Macrophages During Callus Formation and Maturation Reveals Close Crosstalk Between Macrophages and Newly Forming Vessels. Front Immunol. 2019;10: 2588. doi: 10.3389/fimmu.2019.02588.
  3. Holzwarth K, Kohler R, Philipsen L, Tokoyoda K, Ladyhina V, Wahlby C, Niesner RA, Hauser AE. Multiplexed fluorescence microscopy reveals heterogeneity among stromal cells in mouse bone marrow sections. Cytometry A. 2018;93: 876-888. doi: 10.1002/cyto.a.23526.
  4. Solis AG, Bielecki P, Steach HR, Sharma L, Harman CCD, Yun S, de Zoete MR, Warnock JN, To SDF, York AG, Mack M, Schwartz MA, Dela Cruz CS, Palm NW, Jackson J, Flavell RA. Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature. 2019; 573: 69-74. doi: 10.1038/s41586-019-1485-8.
  5. Lindquist RL, Bayat-Sarmadi J, Leben R, Niesner R, Hauser AE. NAD(P)H Oxidase Activity in the Small Intestine Is Predominantly Found in Enterocytes, Not Professional Phagocytes. Int J Mol Sciences. 2018; 19:1365. doi: 10.3390/ijms19051365.
  6. Ulbricht C, Leben R, Rakhymzhan A, Kirchhoff F, Nitschke L, Radbruch H, Niesner RA, Hauser AE. Intravital quantification of absolute cytoplasmic B cell calcium reveals dynamic signaling across B cell differentiation stages. Elife. 2020; 10:e56020. doi: 10.7554/eLife.56020.

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Our laboratory focuses on the immunological and molecular pathomechanisms of the skin with the aim to identify approaches for personalized and preventive medicine. One group of our translational research interests are chronic inflammatory autoimmune diseases of the skin. In addition to preclinical models and in vitro methods, we use skin and blood samples from patients for biomarker identification. We are particularly interested in specialized T cell responses and cytokine signaling pathways (JAK/STAT).

Project description:

Blistering autoimmune dermatoses (bAD) represent a heterogeneous group of skin diseases characterized by autoantibodies against structural proteins. In pemphigoid diseases, the formation of IgG and, more rarely, IgA/IgM antibodies against hemi desmosomes lead to loss of contact of the lower keratinocyte layer with the basal membrane. Subepidermal cleft formation occurs, resulting in the formation of blisters1. The most common pemphigoid disease of old age is bullous pemphigoid (7/8 LD), followed by rarer variants such as lamin γ1 and scarring mucinous pemphigoid. While B cells are primarily responsible for autoantibody production, T cells appear to play an important role in disease development.

In recent work on the pathogenesis of bAD, we were able to investigate the relationship between specialized T follicular helper (Tfh) cells and autoreactive B cells for the production of autoantibodies in bAD by comprehensive analyses of the immune system (RNA-seq, immunoprofiling, T/B cell cultures)2. In bullous pemphigoid, the risk of disease increases with age without knowing the immunological precursors for this. In this project, we aim to clarify whether specialized Tfh cells and their cytokines differ in healthy individuals and bAD patients in an age-dependent manner. The aim is to investigate their influence on the pathogenesis of the disease and to identify new markers to predict the risk for the manifestation of bAD or even to use them preventively3.

In this project, Tfh populations of peripheral blood will be studied by multiparametric flow cytometry. We are particularly interested in the differences between healthy and bAD patients and the changes in different age decades. Furthermore, the cytokine profile (IL-4, IL-17, IL-21, IL-6, IFN-y) will be investigated4. These results will be compared on the one hand with antibody titers against BP180 and BP230 and on the other hand with transcriptome analyses of healthy and lesional skin (bAD). The goal of the PhD thesis is to determine disease-associated patterns relevant for early detection or risk of manifestation of bAD, by evaluating the Tfh populations, cytokine profile, autoantibody titers and age-related parameters.

Application details

References

  1. Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet. 2019; 394(10201):882-894. doi: 10.1016/S0140-6736(19)31778-7.
  2. Holstein J, Solimani F, Baum C, […], Pfützner W, Ghoreschi K, Möbs C. Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production. J Allergy Clin Immunol. 2020: S0091-6749(20)31624-9. doi: 10.1016/j.jaci.2020.11.008. Epub ahead of print.
  3. Eckardt J, Eberle FC, Ghoreschi K. Diagnostic value of autoantibody titres in patients with bullous pemphigoid. Eur J Dermatol. 2018; 28(1):3-12. doi: 10.1684/ejd.2017.3166.
  4. Li Q, Liu Z, Dang E, […], Yang L, Shi X, Wang G. Follicular helper T Cells (Tfh) and IL-21 involvement in the pathogenesis of bullous pemphigoid. PLoS One. 2013; 8(7):e68145. doi: 10.1371/journal.pone.0068145

Prinicipal Investigator

Dr. Markus Schüler

Scientific interest within the context of the graduate college:

Our research group studies the underlying mechanisms of chronic kidney disease (CKD). Acute and chronic kidney injury has been increasingly recognized as a global public health concern, associated with high morbidity, and mortality. Acute kidney injury is frequent, occurring in 21% of hospital admissions and leads to CKD regardless of the cause. CKD encompasses a group of heterogeneous disorders affecting renal structure and function with a prevalence of 10-15% worldwide1. During the past decades, research into kidney disease has largely focused on identifying causative insults and disease modifiers of renal injury. However, sufficient clarification about the underlying pathophysiological mechanism has not provided yet.

We hypothesize that the ability of the kidney to respond to different stress conditions contributes significantly to the maintenance of normal renal function and structure, whereas an impaired cellular stress responses promotes renal damage. Here, we focus on the so-called “DNA Damage Response” (DDR)2, which relevance for kidney diseases has been demonstrated in individuals with interstitial nephritis caused by monogenic mutations in genes encoding proteins of the DDR complex3. Interestingly, transgenic mice models with a defective DDR response show an increased susceptibility to environmental nephrotoxins, which leads to renal failure and typical histological features of CKD4. Moreover, recently published data argues that DDR functions are critical in disease progression of rare, inherited juvenile nephropathies as evidenced by accumulated DNA damage, that yields to increase apoptosis coupled with profibrotic responses5,6. This projects aims to investigate if an impaired DNA damage response contributes to the renal pathomechanisms of AKI and CKD.

Project description:

In CKD, regardless of its cause, renal fibrosis is the primary determinant of end-stage kidney disease, with no effective therapy available today. Within in scope of this project it is planned to study the response of kidney tubular cells to DNA damage, which may play a role in the pathophysiology of CKD. Therefore, we employed a human in-vitro model using patient derived renal tubular cells from urine samples, which allows investigating the biological impact of DNA damage response signaling. In a comparative approach, cultured renal tubular cells from individuals with CKD and healthy controls will be used to study the cellular response by applying different molecular techniques. In detail, it is planned to evaluate the activity of the DDR pathway targeting e.g. the accumulation of DNA damage, the cell cycle progression, the rate of apoptosis and profibrotic gene expression profiles. This project provides a new cellular model to study disease mechanisms of acute and chronic kidney injury and may offer new understandings about the pathogenesis of CKD.

Application details

References

  1. Eckardt KU, Coresh J, Devuyst O, […], Köttgen A, Levey AS, Levin A. Evolving importance of kidney disease: from subspecialty to global health burden. Lancet. 2013; 382:158-169. doi:10.1016/S0140-6736(13)60439-0.
  2. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010; 40:179-204. doi:10.1016/j.molcel.2010.09.019.
  3. Zhou W, Otto EA, Cluckey A, […], Levy S, Smorgorzewska A, Hildebrandt F. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012; 44:910-915. doi:10.1038/ng.2347.
  4. Airik R, Schueler M, Airik M, […], Mukherjee E, Sims-Lucas S, Hildebrandt F. A FANCD2/FANCI-Associated Nuclease 1-Knockout Model Develops Karyomegalic Interstitial Nephritis. J Am Soc Nephrol. 2016; 27:3552-3559. doi:10.1681/ASN.2015101108.
  5. Chaki M, Airik R, Ghosh AK, […], Smogorzewska A, Otto EA, Hildebrand F. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell. 2012; 150:533-548. doi:10.1016/j.cell.2012.06.028.
  6. Slaats GG, Giles RH. Are renal ciliopathies (replication) stressed out? Trends Cell Biol. 2015; 25:317-319. doi:10.1016/j.tcb.2015.03.005.

Prinicipal Investigator

Scientific interest within the context of the graduate college:

We study development and function of the innate immune system, in particular of innate lymphoid cells (ILC). A current focus is to obtain a molecular understanding of how the innate immune system, by integrating environmental signals, contributes to tissue physiology and health. Recent studies have revealed ever more intriguing relationships between innate immune system components and basic developmental and biologic processes that are likely to reveal unsuspected pathways by which the immune system might be plumbed to improve health and health span. These lines of research have suggested new functions of the immune system for processes such as tissue homeostasis, morphogenesis, metabolism, regeneration and growth. Our research is developing by crossing boundaries of disciplines (immunology, microbiology, developmental biology, stem cell biology, nutrition sciences, tumor biology, regenerative medicine etc.) and is, by nature, highly interdisciplinary.

Project description:

Based on our data, we hypothesize that ILC3 play an important role in directly instructing adaptation of the intestinal organ to changing metabolic needs by affecting programs in epithelial stem cells or their immediate progeny. Available data has interrogated the role of ILC3: stem cell modules in the context of intestinal damage. We wondered if ILC3 are involved in more physiological adaptative processes. One of the biggest challenges to metabolic demands in life is pregnancy. During gestation and lactation, the female organism undergoes major physiological changes to accommodate the developing offspring prominent among them considerable growth of the crypt-villus axis of the small intestine. We have recently developed a sophisticated method to record crypt-villus length and noted that mice lacking ILC3 (i.e., Rorc(gt)Gfp/Gfp mice) do not show pregnancy and lactation-induced epithelial hypertrophy. Interestingly, such absence of intestinal growth led to reduced caloric absorption by enterocytes and reduced caloric content of breast milk.

We hypothesize that ILC3 act on intestinal stem cells enhancing differentiation of enterocytes for increased nutrient absorption. Our research may provide a novel conceptual framework of how tissue and metabolic adaptation can be sustained by ILC3 that may dynamically adjust epithelial cell function to a variety of physiological demands.

Our major goals are (1) to define the role of ILC3 in pregnancy and lactation-induced epithelial hypertrophy on a molecular level, (2) to analyze the impact of ILC3 on stem cell representation, niche population dynamics using stochastic multi-color fate labelling and (3) to understand how ILC3 regulate epithelial cell metabolism and tissue growth during pregnancy and lactation.

Application details

References

  1. Guendel F, Kofoed-Branzk M, Gronke K, […], Mashreghi MF, Kruglov AA, Diefenbach A. Group 3 innate lymphoid cells program a distinct subset of IL-22BP-producing dendritic cells demarcating solitary intestinal lymphoid tissues. Immunity. 2020; 53:1015-1032. doi: 10.1016/j.immuni.2020.10.012.
  2. Schaupp L, Muth S, Rogell L, […],Schild H, Diefenbach A1,*,Probst HC*. Microbiota-induced tonic type I interferons instruct a poised basal state of dendritic cells. Cell. 2020; 181:1080-1096. doi: 10.1016/j.cell.2020.04.022. 1Lead Senior Author; *equal contribution.
  3. Gronke K, Hernández PP, Zimmermann J, […], Glatt H, Triantafyllopoulou A, Diefenbach A. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature. 2019; 566:249-253. doi: 10.1038/s41586-019-0899-7.
  4. Klose CSN, Flach M, Möhle L, […], Dunay IR, Tanriver Y, Diefenbach A. Differentiation of type 1 ILCs from a common progenitor to helper-like innate lymhoid cell lineages. Cell. 2014; 157:340-356. doi: 10.1016/j.cell.2014.03.030.
  5. Klose CSN, Kiss EA, Schwierzeck V, […], Waisman A, Tanriver Y, Diefenbach A. A T-bet gradient controls the fate and function of CCR6 RORγt+ innate lymphoid cells. Nature. 2013, 494:261-265. doi: 10.1038/nature11813.

Prinicipal Investigator

Dr. Nicola Wilck
Dr. Hendrik Bartolomaeus

Scientific interest within the context of the graduate college:

Our laboratory investigates the interaction of dietary factors with the gut microbiota and the host, especially with the host’s immune system, in the context of cardiovascular and renal disease1-4. Arterial hypertension and chronic kidney disease (CKD) are of particular interest, as both conditions are associated with a significantly increased cardiovascular risk. We combine experimental model systems with exploratory clinical studies to better understand the microbiota-host interaction. We aim to use our findings to further define health in this context and to better understand transitions to disease.

CKD is associated with dysregulated immune responses5 and a high cardiovascular risk6. In addition, CKD is associated with changes in the composition and function of the microbiota. Indole metabolites of bacterial origin are of particular interest here, as they can accumulate in the blood with declining renal function and have an immunomodulatory potential3. It is unclear to what extent these CKD-associated microbial changes contribute to cardiovascular risk. To investigate this question, microbiota from CKD patients, as well as from CKD mouse models and healthy control groups will be transplanted into germ-free mice. In the recipients, immunological changes and cardiovascular parameters will be quantified and the molecular mechanisms involved will be investigated in more detail.

Project description:

WP 1: Microbiota transfer from CKD mouse models. Fecal samples from different CKD animal models (incl. healthy controls) will be analyzed (composition, metabolites) and used to colonize germ-free mice. The recipients will then be phenotyped in regard of their immune function (isolation of immune cells from different end organs and analysis by flow cytometry) and cardiovascular function (vascular and cardiac function, intestinal barrier, etc.) and compared with parameters of the donors.

WP2: Microbiota transfer of human-associated microbiota. Stool samples from CKD patients and healthy controls will be collected, analyzed by sequencing (composition, metabolites) and transplanted into germ-free mice. Immunological, microbial and cardiovascular parameters will be analysed between the two groups of recipients and the extent to which human CKD-associated pathologies are transferable to the mouse model will be investigated.

Application details

References

  1. Bartolomaeus H, Balogh A, Yakoub M, […], Muller DN, Stegbauer J, Wilck N. Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage. Circulation. 2019; 139:1407-1421. doi: 10.1161/CIRCULATIONAHA.118.036652.
  2. Wilck N, Balogh A, Marko L, Bartolomaeus H and Muller DN. The role of sodium in modulating immune cell function. Nat Rev Nephrol. 2019; 15:546-558. doi: 10.1038/s41581-019-0167-y.
  3. Wilck N, Matus MG, Kearney SM, […], Linker RA, Alm EJ, Muller DN. Salt-responsive gut commensal modulates TH17 axis and disease. Nature. 2017; 551:585-589. doi: 10.1038/nature24628.
  4. Bartolomaeus H, Avery EG, Bartolomaeus TUP, […], Wilck N, Kushugulova A, Forslund SK. Blood Pressure Changes Correlate with Short-Chain Fatty Acids Production Shifts Under a Synbiotic Intervention. Cardiovasc Res. 2020; 116:1252-1253. doi: 10.1093/cvr/cvaa083.
  5. Sato Y, Yanagita M. Immunology of the ageing kidney. Nat Rev Nephrol. 2019; 15:625-640. doi: 10.1038/s41581-019-0185-9.
  6. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004; 351:1296-305. doi: 10.1056/NEJMoa041031.

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Our research aims to understand the role of tissue-resident cells of the innate immune system in the prevention of chronic inflammatory diseases such as systemic lupus erythematosus and inflammatory bowel disease. Our goal is to identify mechanisms that may inhibit the transition from homeostasis to chronic inflammatory disease and to determine the role of tissue-resident cells of the innate immune system in this process. Understanding such mechanisms may allow to answer the question of why some patients are susceptible to chronic autoimmune-related inflammatory diseases and others are not, and how to improve/achieve resistance to chronic inflammatory diseases.

Project description:

Many patients with chronic inflammatory diseases, such as SLE, suffer from CNS manifestations whose early diagnosis and treatment are very difficult. Interestingly, we find that cells of the innate immune system are activated in the kidney and brain of SLE mouse models before the onset of clinically manifest systemic disease. Our data suggest that tissue-resident macrophages and/or microglia migrate along inflamed vessels of SLE mouse models and drive CNS inflammation. The role of these macrophages in CNS lupus is as yet unknown and will be investigated in this project. The project is linked to the Transregio “Neuromac” TRR167 (participating universities: Freiburg University Hospital, Weizman Institute of Science, Israel and Charité – Universitätsmedizin, Berlin).

Application details

Prinicipal Investigator

Prof. Dr. Frank Tacke,
Dr. Linda Hammerich

Scientific interest within the context of the graduate college:

Our lab studies the role of immune cells and inflammatory processes in the liver. Infiltration and activation of immune cells play an important role during the development of acute and chronic liver diseases, but the exact molecular and cellular mechanisms leading to the development of liver inflammation have not been fully elucidated until now. We are exploring the inflammatory processes during acute liver failure, non-alcoholic fatty liver disease and steatohepatitis (NASH), liver cirrhosis and liver cancer in order to develop new diagnostic and therapeutic strategies. Furthermore, a better understanding of how both pro- and anti-inflammatory pathways can disrupt the homeostatic processes of a healthy liver is critical for the prevention of liver diseases in the first place.

During homeostasis the liver plays an important role in adaptation to environmental influences as it is constantly exposed to antigens from the gastrointestinal system, and plays a critical role in maintaining a balance between tolerance to harmless antigens (eg. food proteins or commensal bacteria) and control of pathogens1. When this balance is disrupted (termed maladaptation) the resulting immune-mediated changes can lead to chronic liver diseases and ultimately cancer.

Project description:

We are especially interested in characterizing the microenvironment of gastrointestinal tumors, because these tumors usually develop under chronic inflammatory conditions but then often switch to an immunosuppressive environment2. This makes them insusceptible to many therapeutic strategies including immunotherapies, which are emerging as new treatment strategies for many types of cancer3,4. In order to better understand how this switch happens and how the immune-microenvironment in the tumor can be influenced by the surrounding tissue and vice versa, this project aims at investigating the immune phenotype of gastrointestinal tumors. Tumor samples from patients with gastrointestinal tumors (eg. hepatocellular carcinoma, neuroendocrine tumors) as well as chronic liver diseases (eg. NASH, NAFLD) will be analyzed using high throughput single cell technologies, including single cell RNA-sequencing, spectral flow cytometry and multiplex immunohistochemistry. All techniques are already set up in our lab5,6 and will be used to analyze samples already available in a biobank in our department as well as prospectively acquired tissue samples obtained during surgery (resections, explants). Characterization of the peri-/intratumoral immune cell populations and correlation with clinical data (underlying etiology, medical history, therapy response, survival time etc.) will contribute to our understanding of the immune microenvironment in gastrointestinal tumors and how this influences disease outcome. These data will be critical to develop novel strategies to prevent chronic inflammatory liver diseases and tumor formation as well as guide development of personalized therapeutic strategies and future clinical trials.

Application details

References

  1. Kubes P, Jenne C. Immune Responses in the Liver. Annu Rev Immunol. 2018; 36: 247-277. doi: 10.1146/annurev-immunol-051116-052415.
  2. Rohr-Udilova N, Klinglmüller F, Schulte-Hermann R, […], Jensen-Jarolim E, Eferl R, Trauner M. Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma. Sci Rep. 2018; 8:6220. doi: 10.1038/s41598-018-24437-5.
  3. Zhu AX, Finn RS, Edeline J, […], Siegel AB, Cheng AL, Kudo M, KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018; 19: 940-952. doi: 10.1016/S1470-2045(18)30351-6.
  4. Brahmer JR, Tykodi SS, Chow LQM, […], Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366:2455-2465., doi: 10.1056/NEJMoa1200694.
  5. Ramachandran P, Dobie R, Wilson-Kanamori JR, […], Marioni JC, Teichmann SA, Henderson NC. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. 2019; 575:512-518. doi: 10.1038/s41586-019-1631-3.
  6. Guillot A, Kohlhepp MS, Bruneau A, Heymann F, Tacke F. Deciphering the Immune Microenvironment on A Single Archival Formalin-Fixed Paraffin-Embedded Tissue Section by An Immediately Implementable Multiplex Fluorescence Immunostaining Protocol. Cancers (Basel). 2020; 12:2449. doi: 10.3390/cancers12092449..

Prinicipal Investigator

Scientific interest within the context of the graduate college:

My lab is interested in understanding the role of macrophages in homeostasis and disease. Immune complex (IC)-mediated pathologies encompass a range of acute or chronic clinical conditions (e.g., post-streptococcal glomerulonephritis, systemic lupus erythematosus) that affect millions of people worldwide and have a very high socioeconomic burden1. IC-mediated pathologies often target the kidney and cause inflammation that could progress to end-stage renal failure and the need for dialysis or transplantation2. Infiltration of myeloid cells is one of the most striking features of renal inflammation caused by IC and correlates with poor patient prognosis3,4, yet experimental evidences of the functions of various myeloid cell subsets in the pathogenesis of these diseases are sparse. A better understanding of their mechanistic basis is needed to develop new, more specific treatments. Our previous work has provided evidence that the macrophages residing in the renal interstitium, termed kidney resident macrophages (krMΦs), scavenge IK and trigger the inflammatory response against circulating IC in the kidney5. However, it is unclear how this inflammatory response triggers tissue injury and whether the tissue injury is mediated by krMΦs or other infiltrating myeloid cells. Therefore, the subject of this investigation will be to determine what roles krMΦs and infiltrating myeloid cells (i.e., monocytes and neutrophils) play in acute IC-mediated renal inflammation to maintain renal health.

Project description:

Two groups of mice are compared with each other: one group is injected with IC (IgG+antigen); a second group is injected with antigen. After different time points, the resident and migrated myeloid cells in both groups will be examined for (i) immunophenotyping of the cells, (ii) characterization their cytokine/chemokine production, and (iii) their localization. Our hypothesis is that the myeloid cells develop a pro-inflammatory phenotype as a result of acute IC-mediated nephritis.

Aim 2: Analysis of stromal cells and tissue injury in acute IC-mediated nephritis. The same two groups of mice as in Aim 1 will be analyzed to investigate (i) the phenotype and (ii) the associated injury to epithelial cells (i.e. renal tubules) and endothelial cells.

Application details

References

  1. Schifferli JA, Taylor RP. Physiological and pathological aspects of circulating immune complexes. Kidney Int. 1989; 35:993-1003. doi: 10.1038/ki.1989.83.
  2. Tecklenborg J, Clayton D, Siebert S, Coley SM. The role of the immune system in kidney disease. Clin Exp Immunol. 2018; 192:142-150. doi: 10.1111/cei.13119.
  3. Kluth DC, Erwig LP, Rees AJ. Multiple facets of macrophages in renal injury. Kidney Int. 2004; 66:542-557. doi: 10.1111/j.1523-1755.2004.00773.x.
  4. Hill GS, Delahousse M, Nochy D, Rémy P, Mignon F, Méry JP, Bariéty J. Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages. Kidney Int. 2001; 59:304-316. doi: 10.1046/j.1523-1755.2001.00492.x.
  5. Stamatiades EG, Tremblay ME, Bohm M, […], Diebold S, Nimmerjahn F, Geissmann F. Immune Monitoring of Trans-endothelial Transport by Kidney-Resident Macrophages. Cell. 2016; 166:991-1003. doi: 10.1016/j.cell.2016.06.058.

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Helicobacter pylori is a human-specific bacterium that colonizes the stomachs of about 50% of the world’s population. We have previously found that H. pylori can invade gastric glands and colonize stem cell compartment1. This subpopulation of H. pylori induces an altered stem cell behavior. The stem cells increase their turnover kinetics, and in parallel promote a production of antimicrobial cells that secrete various antimicrobial compounds, that in turn shield the stem cells from invading bacteria. This counterbalances infection, while at the same time promoting changes in gland proliferation and cellular composition2,3. These data demonstrate the remarkable potential of our gastrointestinal epithelial lining to adapt to changes in the environment. The mechanisms that enable such adaptation have not been explored in detail and we have generated a substantial amount of preliminary data that will be used as a solid basis for this project (Jablonska et al., in revision). Using our Helicobacter model we would like to not only generate important insights in pathogenesis of gastric disorders, but to also generate fundamental, more general insights into the ability of mucosal tissues to respond to changes in the environment. In fact, we hypothesize that the behavior of stem cells already in the healthy state is significantly shaped by microbes and that the tissue structure, that we consider healthy, is under control of bacteria and their products.

Figure 1. Stem Cells are colonized by and respond to H. pylori.
a) Confocal microscopy of gland-associated H. pylori 2 weeks after infection (arrow indicates single bacteria in the base, where stem cells reside); b) Single molecule in situ hybridization (ISH) for Axin2 in the mouse stomach; c) 6-week lineage tracing in the antrum of Axin2CreER/Rosa-tdTomato (red: Axin2+ cell derived clones); d) Single molecule ISH for Rspo3 in uninfected and 2 month-infected mouse antrum; e) Axin2 expression in uninfected and 2 month-infected mouse antrum; f) Schematic demonstrating how gland-associated bacteria trigger Rspo3 –driven Axin2+ stem cell proliferation.
(Figure 1a from Sigal et al., 2015 Gastroenterology; Fig. 1b,d,e from Sigal et al., Nature 2017)

Project description:

The aim of the project will be to characterize the intercellular communication that promotes the mucosal response to H. pylori. We will combine well-established tools and novel techniques such as scRNAseq and spatial transcriptomics in collaboration with experts from the Berlin Institute for Medical Systems Biology. We will use organoids grown from primary gastric epithelial cells, in vivo infection models as well as human material from patients infected with H. pylori to explore how stem cells respond to Helicobacter infection. Our preliminary data suggest that the epithelial stem cells are primed to recognize and respond to infections and we will use various tools to explore this idea, characterize molecular pathways that control it and to address how such priming influences epithelial responses to infections.

Application details

References

  1. Sigal M, Rothenberg ME, Logan CY, […], Nusse R, Torres J, Amieva MR. Helicobacter pylori Activates and Expands Lgr5(+) Stem Cells Through Direct Colonization of the Gastric Glands. Gastroenterology. 2015; 148:1392-404.e21. doi: 10.1053/j.gastro.2015.02.049.
  2. Sigal M, Logan CY, Kapalczynska M, […], Nusse R, Amieva MR, Meyer TF. Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis. Nature. 2017; 548:451-455. doi: 10.1038/nature23642.
  3. Sigal M, Del Mar Reinés M, Müllerke S, […], Wiedenmann B, Sauer S, Meyer TF. 3 induces secretory, antimicrobial Lgr5 + cells in the stomach. Nat Cell Biol. 2019; 21:812-823. doi: 10.1038/s41556-019-0339-9.

Prinicipal Investigator

Project description:

Resilience to infections is equally defined by the host’s ability to clear the infecting pathogen and to resolve and mitigate secondary injury, and thus to restore and maintain tissue homeostasis. These physiological processes of resolution and repair, however, intersect with pathogenic responses in chronic organ fibrosis. The role of viral infections in fibrotic diseases are not well defined. We have recently identified a population of pulmonary macrophages that arises in patients with severe COVID19 and fibroproliferative ARDS. These macrophages share core features with profibrotic macrophages in idiopathic pulmonary fibrosis or liver cirrhosis. Here we aim to dissect the signals that program profibrotic monocyte and macrophage responses in acute infections and chronic fibrosis in order to define checkpoints and potential therapeutic targets, with the aim of rewiring responses to tissue injury and restoring tissue homeostasis.

Application details

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Chronic inflammatory disorders are triggered and maintained by effector mediators produced by the adaptive immune system, such as T cell and B cells. In T cells, inflammatory programs are induced by the T cell receptor (TCR) in conjunction with distinct cytokines and/or environmental signals. Recently, it appeared evident that emerging innate cell subsets lacking the TCR and collectively known as innate lymphoid cells (ILCs), exhibit a similar heterogeneity of effector modules. ILCs are not only activated in the course of inflammation but colonize different organs already during embryonic development and contribute to tissue homeostasis. The signals, developmental pathways and innate receptors instructing the different effector programs and their execution in ILCs remain largely unknown. Therefore, our main research focus is devoted to study the transcriptional networks and the innate modules employed by ILCs to modulate tissue homeostasis and initiate inflammation.

Project description:

RORgt+ ILCs play a crucial role in driving fetal formation of lymph nodes and in promoting intestinal barrier homeostasis1. In our previous work, we have identified human ILC progenitors in tissues and described a transcriptional network contributing to promote lymphoid organ formation and intestinal homeostasis besides RORgt2-3. Using a combination of single cell sequencing techniques, in vitro cultures and in vivo analysis already established in the group, this project aims to define in detail the molecular dynamics underlying this transcriptional network governing ILC differentiation in the human and murine intestine.

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References

  1. Juelke K, Romagnani C. Differentiation of human innate lymphoid cells (ILCs). Curr Opin Immunol. 2016; 38:75-85. doi: 10.1016/j.coi.2015.11.005.
  2. Montaldo E, Teixeira-Alves LG, Glatzer T, […], Moretta L, Mingari MC, Romagnani C. Human RORγt(+)CD34(+) cells are lineage-specified progenitors of group 3 RORγt(+) innate lymphoid cells. Immunity. 2014; 41:988-1000. doi: 10.1016/j.immuni.2014.11.010.
  3. Stehle et al, under revision

Prinicipal Investigator

Prof. Dr. Marcus A. Mall
Dr. Markus Bardua

Scientific interest within the context of the graduate college:

Biomarkers play a central role in detecting chronic inflammatory diseases before irreversible tissue damage occurs. These measurable, ideally disease-specific, indicators can be detected in the organism even before the onset of symptoms. For example, neutrophil elastase (NE), a serine protease secreted by activated neutrophils and essential for the innate immune response to pathogen infections, already serves as a biomarker for certain chronic inflammatory diseases of the respiratory and digestive tracts. In these cases, the activity of secreted, i.e. “free” NE, which is released during chronic inflammatory processes and damages tissues due to proteolytic activity, has been determined so far. In previous work, we have shown that NE also occurs membrane-bound on the surface of activated neutrophils in the airways of chronic inflammatory lung diseases such as cystic fibrosis. There, membrane-bound NE is already catalytically active long before the activity of free NE can be detected and it is involved in airway damage1,2. The results of these studies suggest that determining the activity of membrane-bound NE could also enable earlier diagnosis of other chronic inflammatory diseases and facilitate personalized therapy.

Project description:

The aim of this translational research project is to investigate the role of membrane-bound NE activity on neutrophils circulating in the blood of healthy subjects and patients with chronic inflammatory (autoimmune) diseases in childhood and thus establish a method for early disease detection. For this purpose, a reporter molecule based on Förster resonance energy transfer (FRET) technology we developed is used3. This allows the detection of NE activity on the surface of living, freshly isolated cells ex vivo using flow cytometry. In addition to state of the artcytometry and cell biology technologies, this experimental MD thesis also applies basic molecular biology laboratory work and microscopy and correlates experimental data with clinical patient data on disease progression.

Application details

References

  1. Gehrig S, Duerr J, Weitnauer M, […], Dalpke AH, Schultz C, Mall MA. Lack of neutrophil elastase reduces inflammation, mucus hypersecretion, and emphysema, but not mucus obstruction, in mice with cystic fibrosis-like lung disease. Am J Respir Crit Care Med. 2014; 189:1082-1092. doi: 10.1164/rccm.201311-1932OC.
  2. Dittrich AS, Kühbander I, Gehrig S, […], Herth F, Schultz C, Mall MA. Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis.Eur Respir J. 2018; 51:1701910. doi: 10.1183/13993003.01910-2017.
  3. Hagner M, Frey DL, Guerra M, […], Herth FJF, Schultz C, Mall MA. New method for rapid and dynamic quantification of elastase activity on sputum neutrophils from patients with cystic fibrosis using flow cytometry. Eur Respir J. 2020; 55:1902355. doi: 10.1183/13993003.02355-2019.

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. In Germany, more than 5 million patients suffer from OAand there is no effective treatment1. Among several risk factors for OA development, age has the greatest influence2. In parallel, individuals who bear joint injury are at substantially increased risk of OA, the so-called posttraumatic OA (PTOA)3. However, the signaling pathways that propagate the pathogenic aspects of age and trauma are ill defined. Cellularly, the alteration of chondrocyte biology plays a key role in OA pathogenesis4. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can function as agonist of Toll-like-receptors (TLR). We have found that chondrocytes adapt to this setting by enhanced TLR signaling, which results in impaired matrix generation and energy deficit. This suggests that individuals with high TLR activity in chondrocytes have an increased risk of OA.

However, chondrocytes are not a homogenous population. Classically, according to their cartilage zonal locations, chondrocytes are subdivided into superficial, middle, and deep zone chondrocytes. These zonal subsets exhibit distinct transcriptome profiles5. Our recent scRNAseq analysis, together with two other studies, of human chondrocytes revealed an even higher heterogeneity and identified seven subsets6. Importantly, the composition of these subsets varies during OA progression6. Thus, we aim to effectively manipulate human chondrocytes in vivo in order to regenerate and restore cartilage integrity. Therefore, we seek to identify the evolution of the transcriptional programs of chondrocytes, with a particular focus on TLR signaling, during ageing and PTOA development at single-cell resolution. We plan to perform scRNAseq analysis of chondrocytes isolated from individuals (5 each) of young healthy (YH), PTOA, old healthy (OH), and old age-related OA (OAOA). Herewith we will address ① an overall chondrocyte compositional alteration during ageing and OA development; ② whether TLR and its signaling components qualify as risk factor of (PT)OA and hence whether TLR signaling inhibition may prevent OA progression; ③ the design of a treatment strategy to specifically deliver the inhibitory agents to the TLR-expressing chondrocyte subsets and/or TLR-expressing cartilage zones.

Application details

References

  1. Grifka J, Ogilvie-Harris DJ. Osteoarthritis: Fundamentals and Strategies for Joint-Preserving Treatment. Springer. 2010.
  2. Martel-Pelletier J, Barr AJ, Cicuttini FM, […], Jones G, Teichtahl AJ, Pelletier JP. Osteoarthritis. Nat Rev Dis Primers. 2016; 2:16072. doi: 10.1038/nrdp.2016.72.
  3. Jiménez G, Cobo-Molinos J, Antich C, López-Ruiz E. Osteoarthritis: Trauma vs Disease. Adv Exp Med Biol. 2018; 1059:63-83. doi: 10.1007/978-3-319-76735-2_3.
  4. Sook Hwang H, Kim HA. Chondrocyte Apoptosis in the Pathogenesis of Osteoarthritis. Int J Mol Sci. 2015; 16:26035-26054. doi: 10.3390/ijms161125943.
  5. Grogan SP, Duffy SF, Pauli C, […], Su AI, D´Lima DD, Lotz MK. Zone-specific Gene Expression Patterns in Articular Cartilage. Arthritis Rheum. 2013; 65:418-428. doi: 10.1002/art.37760.
  6. Ji Q, Zheng Y, Zhang G, […], Xu Y, Wang Y, Tang F. Single-cell RNA-seq Analysis Reveals the Progression of Human Osteoarthritis. Ann Rheum Dis. 2019; 78(1):100-110. doi: 10.1136/annrheumdis-2017-212863.

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Pulmonary hypertension (PH) is the leading symptom of diseases characterized by an increase in mean pulmonary arterial blood pressure. PH increases right ventricular stress and ultimately leads to potentially fatal right heart failure. Hence, the mean survival time after PH diagnosis is only three years in the absence of therapy. At the histological level, PH is characterized by structural vascular remodeling in the lung that is evident as muscularization of arterioles and hyperproliferation of endothelial cells. Despite extensive research, no causal therapy for PH exists up to now. Rather, approved drugs only delay disease progression, which ultimately ends in most cases with lung transplantation or death. This poor prognosis illustrates the need to investigate underlying molecular pathomechanisms of PH in order to identify causal and targeted treatment strategies.

In an ongoing research project, we identified a potential candidate for such a causal therapy: the primary cilium. The primary cilium is an organelle that extends as a protrusion of the cell membrane into the extracellular space and functions as a chemo- and mechanosensor. In PH, we detected a shortening and loss of the primary cilium in pulmonary artery endothelial and smooth muscle cells by a so far unknown mechanism. Our in vitro experiments show that a respective cilium loss increases proliferation and migration of endothelial and smooth muscle cells. These results identify a dysregulation of the primary cilium in PH, which is expected to contribute to vascular remodeling and thus, disease progression. Hence, therapies promoting cilium elongation or reciliation could possibly slow down or even prevent vascular remodeling and PH. However, the signal pathways regulating the primary cilium in PH are so far unknown.

Project description:

To address this topic, we aim to investigate first in vitro whether and how candidate-signaling pathways including mTOR, PDGF, TGF-β and NO are regulated by deciliation in pulmonary arterial endothelial and smooth muscle cells. Next, we will test in which way these signaling pathways regulate cell ciliation as well as cellular responses characteristic of PH, including cell proliferation, migration, smooth muscle hypertrophy, and endothelial-to-mesenchymal transition. In a second step, we will test whether cilium elongation by repurposing of already approved drugs may inhibit the activation of these signaling pathways and thus, cellular responses characteristic of PH. Finally, the obtained insights into the regulation of the primary cilium and its effects on cellular responses in PH will be translated to preclinical in vivo models of PH in mice and rats with the aim to develop and validate novel therapeutic treatment strategies for PH. As such, the outcome of the proposed work is expected to yield important new insights into cellular and molecular mechanisms of health and disease, and in parallel to generate tangible improvements in medical care for a fatal illness that can hitherto only be treated symptomatically.

Application details

Prinicipal Investigator

Prof. Dr. Felix Knauf,
PD Dr. Martin Reichel,
Dr. Nicola Wilck

Scientific interest within the context of the graduate college:

Our laboratory focuses on the mechanisms involved in maintaining oxalate homeostasis. Oxalate is a component of various foods, found in different vegetables, nuts, but also in tea and coffee. High urinary oxalate concentrations lead to kidney stones, the second most common kidney disease after hypertension. Oxalate represents the most common component of kidney stones. When kidney function is reduced as part of chronic kidney disease, for example as a result of diabetes or hypertension, oxalate concentrations in the blood also increase. This is associated with various organ damage and increased cardiovascular mortality (manuscript in revision).

Our research group has cloned the first oxalate transporter (SLC26A6)1. SLC26A6 is expressed in different organs. The transporter is located on the apical side of epithelia and actively secretes oxalate into the intestinal lumen2 and urine3,4. Via this transport process, the oxalate concentration in the body is kept low. In the absence of the transporter, there is increased uptake of oxalate from the intestine and consequent formation of kidney stones5 and progressive kidney damage6. Several research groups have also shown that oxalate can activate immune cells7. Recently, we demonstrated that the oxalate transporter SLC26A6 is widely expressed in immune cells (unpublished data).

Project description:

The subject of the investigation will be the question of what influence an oxalate-containing diet has on the intestinal epithelium and what role immune cells and SLC26A6 play in the recognition of dietary oxalate. Our hypothesis is that dietary oxalate modifies the intestinal epithelial composition to enhance the shift of cytoplasmic SLC26A6 to the epithelium membrane and this process may depend on recognition of oxalate by immune cells.

WP 1: Characterization of the intestinal epithelium during an oxalate-containing diet. Two groups of mice are compared. One group receives an oxalate-free diet; a second group contains an oxalate-containing diet. After three weeks, both groups are analyzed for the following parameters: (i) microbiome composition, (ii) intestinal epithelium characterization (absorptive/secretory cells), (iii) SLC26A6 transporter expression (absorptive/secretory cells).

WP 2: Immunophenotyping of the intestine after an oxalate diet. The same two groups of mice as in WP 1 and additionally SLC26A6-/- mice will be examined for resident and migrated immune cells in (i) intestine and (ii) kidney.

Application details

References

  1. Knauf F, Yang CL, Thomson RB, Mentone SA, Giebisch G, Aronson PS. Identification of a chloride-formate exchanger expressed on the brush border membrane of renal proximal tubule cells. Proc Natl Acad Sci U S A. 2001; 98:9425-9430. doi:10.1073/pnas.141241098.
  2. Neumeier LI, Thomson RB, Reichel M, Eckardt KU, Aronson PS, Knauf F. Enteric Oxalate Secretion Mediated by Slc26a6 Defends against Hyperoxalemia in Murine Models of Chronic Kidney Disease. J Am Soc Nephrol. 2020. 31:1987-1995. doi:10.1681/ASN.2020010105.
  3. Knauf F, Ko N, Jiang Z, […], Van Ittalie CM, Anderson JM, Aronson PS. Net intestinal transport of oxalate reflects passive absorption and SLC26A6-mediated secretion. J Am Soc Nephrol. 2011; 22:2247-2255. doi:10.1681/ASN.2011040433.
  4. Knauf F, Thomson RB, Heneghan JF, […], Egan ME, Alper SL, Aronson PS. Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion. J Am Soc Nephrol. 2017; 28:242-249. doi:10.1681/ASN.2016030279.
  5. Jiang Z, Asplin JR, Evan AP, […], Nottoli TP, Binder HJ, Aronson PS. Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6. Nat Genet. 2006; 38:474-478. doi:10.1038/ng1762.
  6. Knauf F, Asplin JR, Granja I, […], David RJ, Flavell RA, Aronson PS. NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. Kidney Int. 2013; 84:895-901. doi:10.1038/ki.2013.207.
  7. Knauf F, Brewer JR, Flavell RA. Immunity, microbiota and kidney disease. Nat Rev Nephrol. 2019; 15:263-274. doi:10.1038/s41581-019-0118-7.

Prinicipal Investigator

Scientific interest within the context of the graduate college:

The mammalian gastrointestinal tract contains the largest number of immune cells and harbors a large and diverse population of commensal bacteria that exist in a symbiotic relationship with the host1,2. The gut-resident immune cells are separated from our microbial residents by a single layer of intestinal epithelial cells (IEC). The dynamic cross-talk between IEC, the intestinal microbiota, and local immune cells represents a cornerstone of intestinal homeostasis3,4. The balance between the various immune cell populations and tonic cytokine signals play an important role in determining thresholds of tolerance and immunity in the intestine.

Project description:

We recently highlighted the relevance of Oncostatin M (OSM) in intestinal inflammation5. OSM is a pleiotropic cytokine belonging to the interleukin 6 (IL-6) family, which influences numerous homoeostatic and pathological processes in various organs, yet its biology remains obscure6,7. OSM receptor (OSMR) is widely expressed at both tissue (vascular system, heart, lung, adipose tissue, skin, bladder, mammary tissue, adrenal gland, and prostate) and cellular levels (endothelial, smooth muscle, fibroblast, and lung epithelial cells). In contrast, OSM is expressed in multiple hematopoietic cell types including activated monocytes/macrophages, neutrophils, dendritic cells, and T cells. We showed recently that OSMR is widely expressed by stromal and endothelial cells in the intestine; however, the role of OSM in the maintenance of intestinal homeostasis remains unknown. We hypothesize that microbiota-derived local cues induce constitutive OSM expression by gut-resident immune cells to promote intestinal homeostasis by acting on both stromal and endothelial cell compartments. This project will exploit new reporter mouse lines generated in Hegazy lab, gnotobiotic mice, and primary human tissue samples to explore the signals regulating OSM expression in the gut and how OSM functions as a potential tissue rheostat. The project will utilize different cellular and molecular biology techniques, including magnetic cell isolation, flow cytometry, gene expression analysis, RNA sequencing, and histology.

Application details

References

  1. Belkaid Y, Hand TW. Role of the Microbiota in Immunity and Inflammation. Cell. 2014; 157:121-141. doi: 10.1016/j.cell.2014.03.011.
  2. Macpherson AJ, Slack E, Geuking MB, McCoy KD. The mucosal firewalls against commensal intestinal microbes. Semin Immunopathol. 2009; 31:145-149. doi: 10.1007/s00281-009-0174-3.
  3. Hooper LV, Littman DR, Macpherson AJ. Interactions Between the Microbiota and the Immune System. Science. 2012; 336:1268-1273. doi: 10.1126/science.1223490.
  4. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014; 14:141-153. doi: 10.1038/nri3608.
  5. West NR, Hegazy AN, Owens BMJ, […], Keshav S, Travis SPL, Powrie F. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat Med. 2017; 23:579-589. doi: 10.1038/nm.4307.
  6. Richards CD. The Enigmatic Cytokine Oncostatin M and Roles in Disease. ISRN Inflamm. 2013: 512103, doi: 10.1155/2013/512103. doi: 10.1155/2013/512103.
  7. West NR, Owens BMJ, Hegazy AN. The oncostatin M-stromal cell axis in health and disease. Scand J Immunol. 2018; 176:e12694. doi: 10.1111/sji.12694.