Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury
Irina A. Leaf, … , William A. Altemeier, Jeremy S. Duffield
Irina A. Leaf, … , William A. Altemeier, Jeremy S. Duffield
Published November 21, 2016
Citation Information: J Clin Invest. 2017;127(1):321-334. https://doi.org/10.1172/JCI87532.
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Research Article Inflammation Nephrology

Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury

Abstract

Fibrotic disease is associated with matrix deposition that results in the loss of organ function. Pericytes, the precursors of myofibroblasts, are a source of pathological matrix collagens and may be promising targets for treating fibrogenesis. Here, we have shown that pericytes activate a TLR2/4- and MyD88-dependent proinflammatory program in response to tissue injury. Similarly to classic immune cells, pericytes activate the NLRP3 inflammasome, leading to IL-1β and IL-18 secretion. Released IL-1β signals through pericyte MyD88 to amplify this response. Unexpectedly, we found that MyD88 and its downstream effector kinase IRAK4 intrinsically control pericyte migration and conversion to myofibroblasts. Specific ablation of MyD88 in pericytes or pharmacological inhibition of MyD88 signaling by an IRAK4 inhibitor in vivo protected against kidney injury by profoundly attenuating tissue injury, activation, and differentiation of myofibroblasts. Our data show that in pericytes, MyD88 and IRAK4 are key regulators of 2 major injury responses: inflammatory and fibrogenic. Moreover, these findings suggest that disruption of this MyD88-dependent pathway in pericytes might be a potential therapeutic approach to inhibit fibrogenesis and promote regeneration.

Authors

Irina A. Leaf, Shunsaku Nakagawa, Bryce G. Johnson, Jin Joo Cha, Kristen Mittelsteadt, Kevin M. Guckian, Ivan G. Gomez, William A. Altemeier, Jeremy S. Duffield

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Figure 1

TLR2/4– and MyD88-dependent injury responses in pericytes.

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TLR2/4– and MyD88-dependent injury responses in pericytes. (A and B) Enr...
(A and B) Enrichment analysis of biological process ontology in human biopsies from acute kidney injury (AKI) patients compared with healthy controls (A) and myofibroblasts from control and kidneys with acute injury (B). Innate immune–related pathways are highlighted in red. The x axis of the graph shows −log P values calculated using t test for the enrichment of a specific pathway. ECM, extracellular matrix. (C) RNA expression levels of Il6 in pericytes, macrophages, and epithelial and endothelial cells. Translated RNA was isolated from unilateral IRI (U-IRI) and sham control kidneys 24 hours after injury. The y axis shows normalized intensity for Il6 transcript in microarrays; n = 3 per group. (D) Cytokine concentration in supernatants from cultured pericytes 24 hours after stimulation with TLR ligands. (E) Secretion in WT or Myd88–/– pericytes 24 hours after treatment with LPS. (F) Transcriptional response of pericytes to diseased kidney DAMPs at 6 hours. (G) Cytokine concentration in supernatants of WT, Myd88–/–, or Tlr2/4DKO pericytes in response to diseased kidney DAMPs at 24 hours. (H) Western blot of kidney DAMPs. (I and J) IL-6 and MCP-1 concentration in supernatants of WT, Tlr4–/–, TLR2/4DKO, and Myd88–/– pericytes treated with either total histones, histone H4, or HMGB1 for 24 hours. (K) Effect of silencing of Tlr4 or Tlr2 on pericyte response to kidney DAMPs. (n = 3–6 per group; *P < 0.05, 1-way and 2-way ANOVA, Bonferroni’s multiple comparisons test.)