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 January 3, 2017; First 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 5

Role of IRAK4 in pericytes and its inhibition in vitro by BIIB-IRAK4i.

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Role of IRAK4 in pericytes and its inhibition in vitro by BIIB-IRAK4i. (...
(A) Irak4 transcript levels in pericytes after treatment with either scramble or Irak4-specific siRNA. (B) Il6 transcript levels in control and Irak4 knockdown (KD) pericytes 24 hours after treatment with LPS. (C) Il6, Col1a1, and Acta2 expression in control and Irak4 KD pericytes 24 hours after TGF-β treatment. (D–H) Inhibition of injury responses by IRAK4 inhibitor BIIB-IRAK4i in kidney pericytes in vitro. (D and E) Inhibition of IL-6 secretion by mouse kidney pericytes stimulated with LPS (D) or IL-1β (E) in the presence of BIIB-IRAK4i. (F and G) Inhibition of IL6 and CCL2 transcription by human kidney pericytes in response to kidney DAMPs. (H) Inhibition of ACTA2 transcription by human kidney pericytes following TGF-β treatment. (I–L) Inhibition of pericyte migration by IRAK4 inhibitors. (I and K) Representative images of human pericytes stimulated with kidney DAMPs (I) or histones (K) and either vehicle or IRAK4 inhibitors in scratch-wound assays. Blue lines mark the scratch boundaries at 0 hours, and red area designates the scratch at 16 hours. (J and L) Migration scores of DAMP-induced (J) or histone-induced (L) migration. (n = 3–6 per group; *P < 0.05, 2-tailed Student’s t test, 1-way or 2-way ANOVA, Bonferroni’s multiple comparisons test.)