NF-kB signaling in myeloid cells mediates the pathogenesis of immune-mediated nephritis

Samantha A. Chalmers, Sayra J. Garcia, Joshua A. Reynolds, Leal Herlitz, Chaim Putterman

Research output: Contribution to journalArticle

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Abstract

Immune-mediated glomerulonephritis is a serious end organ pathology that commonly affects patients with systemic lupus erythematosus (SLE). A classic murine model used to study lupus nephritis (LN) is nephrotoxic serum nephritis (NTN), in which mice are passively transferred nephrotoxic antibodies. We have previously shown that macrophages are important in the pathogenesis of LN. To further investigate the mechanism by which macrophages contribute to the pathogenic process, and to determine if this contribution is mediated by NF-κB signaling, we created B6 mice which had RelA knocked out in myeloid cells, thus inhibiting classical NF-κB signaling in this cell lineage. We induced NTN in this strain to assess the importance of macrophage derived NF-κB signaling in contributing to disease progression. Myeloid cell RelA knock out (KO) mice injected with nephrotoxic serum had significantly attenuated proteinuria, lower BUN levels, and improved renal histopathology compared to control injected wildtype B6 mice (WT). Inhibiting myeloid NF-κB signaling also decreased inflammatory modulators within the kidneys. We found significant decreases of IL-1a, IFNg, and IL-6 in kidneys from KO mice, but higher IL-10 expression. Flow cytometry revealed decreased numbers of kidney infiltrating classically activated macrophages in KO mice as well. Our results indicate that macrophage NF-κB signaling is instrumental in the contribution of this cell type to the pathogenesis of NTN. While approaches which decrease macrophage numbers can be effective in immune mediated nephritis, more targeted treatments directed at modulating macrophage signaling and/or function could be beneficial, at least in the early stages of disease.

Original languageEnglish (US)
JournalJournal of Autoimmunity
DOIs
StateAccepted/In press - Jan 1 2019

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Nephritis
NF-kappa B
Myeloid Cells
Macrophages
Knockout Mice
Kidney
Lupus Nephritis
Serum
Blood Urea Nitrogen
Cell Lineage
Glomerulonephritis
Proteinuria
Systemic Lupus Erythematosus
Interleukin-10
Disease Progression
Interleukin-6
Flow Cytometry
Pathology
Antibodies

Keywords

  • Lupus nephritis
  • Macrophages
  • Nephrotoxic serum nephritis
  • NF-kappa B
  • RelA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

NF-kB signaling in myeloid cells mediates the pathogenesis of immune-mediated nephritis. / Chalmers, Samantha A.; Garcia, Sayra J.; Reynolds, Joshua A.; Herlitz, Leal; Putterman, Chaim.

In: Journal of Autoimmunity, 01.01.2019.

Research output: Contribution to journalArticle

Chalmers, Samantha A. ; Garcia, Sayra J. ; Reynolds, Joshua A. ; Herlitz, Leal ; Putterman, Chaim. / NF-kB signaling in myeloid cells mediates the pathogenesis of immune-mediated nephritis. In: Journal of Autoimmunity. 2019.
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