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

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

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)321-334
Number of pages14
JournalJournal of Clinical Investigation
Volume127
Issue number1
DOIs
Publication statusPublished - 2017 Jan 3
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Leaf, I. A., Nakagawa, S., Johnson, B. G., Cha, J. J., Mittelsteadt, K., Guckian, K. M., Gomez, I. G., Altemeier, W. A., & Duffield, J. S. (2017). Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury. Journal of Clinical Investigation, 127(1), 321-334. https://doi.org/10.1172/JCI87532