title: 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.forename: Irina A
authors.initials: IA
authors.lastname: Leaf
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Bryce G
authors.initials: BG
authors.lastname: Johnson
authors.forename: Jin Joo
authors.initials: JJ
authors.lastname: Cha
authors.forename: Kristen
authors.initials: K
authors.lastname: Mittelsteadt
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Guckian
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Gomez
authors.forename: William A
authors.initials: WA
authors.lastname: Altemeier
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D005355:Fibrosis; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics
chemical_list: C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse