Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1α-Mediated Inflammatory Disease

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Abstract

Mice carrying a hypomorphic point mutation in thePtpn6gene (Ptpn6spin mice) develop an inflammatory skin disease that resembles neutrophilic dermatosis in humans. Here, we demonstrated that interleukin-1α (IL-1α) signaling through IL-1R and MyD88 in both stromal and immune cells drive inflammation inPtpn6spin mice. We further identified SYK as a critical kinase that phosphorylates MyD88, promoted MyD88-dependent signaling and mediates dermatosis inPtpn6spin mice. Our studies further demonstrated that SHP1 encoded byPtpn6binds and suppresses SYK activation to inhibit MyD88 phosphorylation. Downstream of SHP1 and SYK-dependent counterregulation of MyD88 tyrosine phosphorylation, we have demonstrated that the scaffolding function of receptor interacting protein kinase 1 (RIPK1) and tumor growth factor-β activated kinase 1 (TAK1)-mediating signaling were required to spur inflammatory disease. Overall, these studies identify SHP1 and SYK crosstalk as a critical regulator of MyD88 post-translational modifications and IL-1-driven inflammation.

Skin inflammation observed in a mouse model of neutrophilic dermatosis (Ptpn6spin mice) is instigated by RIPK1 and IL-1α signaling axes, independently of IL-1β and inflammasomes. In this issue, Gurung et al. elucidate the molecular mechanisms underlying RIPK1 and IL-1α mediated inflammatory disease inPtpn6spin mice. SHP1 regulates activation of spleen tyrosine kinase (SYK), which phosphorylates MyD88, to regulate inflammation.

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