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Κυριακή 16 Απριλίου 2017

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

Publication date: Available online 11 April 2017
Source:Immunity
Author(s): Prajwal Gurung, Gaofeng Fan, John R. Lukens, Peter Vogel, Nicholas K. Tonks, Thirumala-Devi Kanneganti
Mice carrying a hypomorphic point mutation in the Ptpn6 gene (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 in Ptpn6spin mice. We further identified SYK as a critical kinase that phosphorylates MyD88, promoted MyD88-dependent signaling and mediates dermatosis in Ptpn6spin mice. Our studies further demonstrated that SHP1 encoded by Ptpn6 binds 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.

Graphical abstract

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Teaser

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 in Ptpn6spin mice. SHP1 regulates activation of spleen tyrosine kinase (SYK), which phosphorylates MyD88, to regulate inflammation.


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