Open Research Projects

The role of kidney-resident macrophages in immune complex-mediated nephritis

Prinicipal Investigator

Scientific interest within the context of the graduate college:

My laboratory is interested in understanding the role of tissue-resident macrophages in homeostasis and disease. Specifically, we are seeking to unravel how kidney-resident macrophages support normal renal function and mediate kidney resilience in inflammation. 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 burden.1 IC-mediated pathologies often target the kidney and cause inflammation that could progress to end-stage renal failure and the need for dialysis or transplantation.2 A better understanding of their mechanistic basis is needed to develop new, more specific treatments.

Project description:

Infiltration of myeloid cells is one of the most striking features of renal inflammation caused by ICs and correlates with poor patient prognosis.3,4 Yet, experimental evidences of the functions of various myeloid cell subsets in the pathogenesis of these diseases are sparse. Our previous work has provided evidence that the macrophages residing in the renal interstitium, termed kidney-resident macrophages (krMΦs), scavenge ICs and trigger the inflammatory response against circulating ICs in the kidney.5 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 project will be to determine what roles krMΦs and infiltrating myeloid cells (i.e., monocytes and neutrophils) play in acute IC-mediated renal inflammation. The student will use in vivo murine models to address the scientific question(s) and reach the project’s milestones(s). Hence, this project is exclusively based on in vivo mouse work. Although training will be provided, the student must be willing to and comfortable to work with murine models. Please note that this project does not offer a ‘stay abroad’ placement.

Aim 1: To investigate the in situ functions of krMΦs and infiltrating myeloid cells in acute IC-mediated nephritis. The student will induce acute IC-mediated nephritis into mice by injecting IC. Control mice will receive PBS. At 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 tissue localization. The student will be trained and acquire expertise in flow cytometry, confocal microscopy, and mouse genetics (e.g. fate-mapping).

Aim 2: Analysis of stromal cells and tissue injury in acute IC-mediated nephritis. The same 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.