Research

The roles of myeloid cells in acute immune complex-mediated nephritis to maintaining renal health

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.