Abstract: FR-PO840
Involvement of Type I Interferon-Responsive Myeloid Cells in Renal Inflammation in a Lupus Mouse Model
Session Information
- Women's Health and Kidney Diseases
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Women's Health and Kidney Diseases
- 2200 Women's Health and Kidney Diseases
Author
- Han, Lindsey, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States
Background
Systemic Lupus Erythematosus (SLE) is an autoimmune disease that damages multiple organs, including the kidneys in Lupus Nephritis (LN). Current treatments for SLE/LN are limited to conventional disease-modifying anti-rheumatic drugs and corticosteroid therapy. A more targeted therapy is necessary to address the underlying disease pathogenesis. Type I interferon (IFN-I) and its receptor (IFNAR) are known to play a significant role in the progression of SLE/LN, making them a major focus of research and therapy.
Methods
3 female mice strains were used to investigate whether deficiency of IFNAR on myeloid cells will drive or reduce disease progression of SLE/LN. The study mice were LysM cre/cre, IFNAR flx/flx B6.Nba2 (n=16) with knockout of IFNAR on myeloid cells (cKO). We also used B6.Nba2 (WT) mice that develop lupus-like disease (n=18) and B6 (C57Bl/6) healthy mice (n=4). The tests performed include flow cytometry on 9 month (9mo) kidney cells, spleen multi-cytokine array of pro-inflammatory cytokines and chemokines, and ELISA of urine biomarkers S100a8, VCAM-1, and PF4.
Results
Kidney 9mo flow data revealed elevated neutrophil and decreased monocytic infiltration in the WT, but normalized levels in cKO, as well as specifically reduced levels of B cells in cKO. CD4+ T cells were specifically reduced, CD8+ T cells were specifically elevated, and Double positive (DP) T cells were normalized in 9mo cKO kidneys. Furthermore, we found that urinary biomarkers S100a8 and PF4 were decreased in 9mo cKO compared to the WT. 9mo spleen IL-21, IL-10, IL-6, IL-4, IFN-γ, and TNF-α were reduced in cKO, and cKO mice developed accelerated Splenomegaly at 2 months, followed by Nephromegaly at 9mo.
Conclusion
In essence, we observed reduced levels of neutrophilic cells, B cells, CD4+ T cells and DP T cells associated with reduced levels of urine biomarkers and that lack of type I interferon expression on myeloid cells affects the trafficking pattern of both monocytic and neutrophilic cells. Thus, our hypothesis for LN development follows: IFNAR facilitates the infiltration of neutrophilic cells, leading to the release of chemokines and the recruitment of inflammatory lymphocytes, and ultimately resulting in renal cell damage and the development of LN. Future directions include further analyses of renal infiltrates and additional urinary biomarkers.