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Updated: Mar 11, 2026

Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice
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Vasodilation of Isolated Vessels and the Isolation of the Extracellular Matrix of Tight-skin Mice

Published on: March 24, 2017

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

Irina A Leaf, Shunsaku Nakagawa, Bryce G Johnson

    The Journal of Clinical Investigation
    |November 22, 2016
    PubMed

    Insights

    Pericytes initiate inflammatory and fibrotic responses via MyD88 and IRAK4 signaling. Inhibiting this pathway in pericytes may treat fibrotic diseases and promote organ regeneration.

    Area of Science:

    • Cell biology
    • Immunology
    • Regenerative medicine

    Background:

    • Fibrotic diseases involve excessive matrix deposition, leading to organ dysfunction.
    • Pericytes, precursors to myofibroblasts, contribute to pathological matrix production and are potential therapeutic targets for fibrogenesis.
    • Tissue injury triggers inflammatory responses involving immune cells and resident cells.

    Purpose of the Study:

    • To investigate the role of pericytes in inflammatory and fibrotic responses following tissue injury.
    • To identify molecular pathways regulating pericyte activation, migration, and differentiation into myofibroblasts.
    • To explore the therapeutic potential of targeting pericyte-specific signaling pathways for fibrotic disease treatment.

    Main Methods:

    • Utilized mouse models of kidney injury.
    • Investigated pericyte activation of Toll-like receptor 2/4 (TLR2/4) and Myeloid differentiation primary response 88 (MyD88) pathways.
    • Examined the activation of the NLRP3 inflammasome and secretion of IL-1β and IL-18.
    • Assessed the impact of MyD88 ablation and IRAK4 inhibition on pericyte function and fibrogenesis in vivo.
    • Analyzed pericyte migration and differentiation into myofibroblasts.

    Main Results:

    • Pericytes activate a TLR2/4- and MyD88-dependent inflammatory program upon tissue injury.
    • Pericytes engage the NLRP3 inflammasome, secreting IL-1β and IL-18, with IL-1β amplifying the response via pericyte MyD88.
    • MyD88 and its downstream kinase IRAK4 are critical intrinsic regulators of pericyte migration and myofibroblast differentiation.
    • Specific pericyte MyD88 ablation or pharmacological IRAK4 inhibition significantly protected against kidney injury by reducing tissue damage and myofibroblast activation/differentiation.

    Conclusions:

    • MyD88 and IRAK4 are key regulators of both inflammatory and fibrogenic responses within pericytes.
    • Targeting the MyD88-dependent pathway in pericytes presents a potential therapeutic strategy to inhibit fibrogenesis and enhance organ regeneration.
    • These findings highlight pericytes as crucial mediators of injury response and potential targets for treating fibrotic conditions.

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