Innate stimuli accentuate end-organ damage by nephrotoxic antibodies via Fc receptor and TLR stimulation and IL-1/TNF-α production

Yuyang Fu, Chun Xie, Jianlin Chen, Jiankun Zhu, Hui Zhou, James Thomas, Xin J. Zhou, Chandra Mohan

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Innate stimuli are well recognized as adjuvants of the systemic immune response. However, their role in driving end-organ disease is less well understood. Whereas the passive transfer of glomerular-targeting Abs alone elicited minimal renal disease, the concomitant delivery of innate stimuli triggered severe nephritis, characterized by proliferative glomerulonephritis with crescent formation, and tubulointerstitial disease. Specifically, stimulating TLR2, TLR3, TLR4, and TLR5 by using peptidoglycan, poly(I: C), LPS, and flagellin, respectively, all could facilitate anti-glomerular Ab-elicited nephritis. In this model, innate and immune triggers synergistically activated several cytokines and chemokines, including IL-1, IL-6, TNF-α, and MCP-1, some of which were demonstrated to be absolutely essential for the development of renal disease. Genetic studies revealed that, whereas the innate trigger is dependent on TLR/IL-1R-associated kinase-mediated signaling, the immune component was contingent on FcR-mediated signals. Importantly, infiltrating leukocytes as well as intrinsic glomerular cells may both serve to integrate these diverse signals. Extrapolating to spontaneous immune-mediated nephritis, although the adaptive immune system may be important in generating end-organ targeting Abs, the extent of damage inflicted by these Abs may be heavily dependent on cues from the innate immune system.

Original languageEnglish (US)
Pages (from-to)632-639
Number of pages8
JournalJournal of Immunology
Volume176
Issue number1
DOIs
StatePublished - Jan 1 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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