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

Prajwal Gurung; Gaofeng Fan; John R Lukens; Peter Vogel; Nicholas K Tonks; Thirumala-Devi Kanneganti

doi:10.1016/j.immuni.2017.03.014

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

Immunity. 2017 Apr 18;46(4):635-648. doi: 10.1016/j.immuni.2017.03.014. Epub 2017 Apr 11.

Authors

Prajwal Gurung¹, Gaofeng Fan², John R Lukens³, Peter Vogel⁴, Nicholas K Tonks², Thirumala-Devi Kanneganti⁵

Affiliations

¹ Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
² Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
³ Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
⁴ Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
⁵ Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: thirumala-devi.kanneganti@stjude.org.

Abstract

Mice carrying a hypomorphic point mutation in the Ptpn6 gene (Ptpn6^spin 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 Ptpn6^spin mice. We further identified SYK as a critical kinase that phosphorylates MyD88, promoted MyD88-dependent signaling and mediates dermatosis in Ptpn6^spin 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.

Keywords: IL-1α; IL-1β; MLKL; MyD88; Ptpn6; RIPK1; RIPK3; SHP1; SYK; TAK1; autoinflammation; myeloid cells; necrosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Flow Cytometry
HEK293 Cells
Humans
Immunoblotting
Inflammation / genetics
Inflammation / immunology*
Inflammation / metabolism
Interleukin-1alpha / genetics
Interleukin-1alpha / immunology*
Interleukin-1alpha / metabolism
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / immunology
MAP Kinase Kinase Kinases / metabolism
Mice, Knockout
Models, Immunological
Mutation
Myeloid Differentiation Factor 88 / genetics
Myeloid Differentiation Factor 88 / immunology*
Myeloid Differentiation Factor 88 / metabolism
Phosphorylation
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / immunology
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / immunology
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Receptors, Interleukin-1 / immunology
Receptors, Interleukin-1 / metabolism
Signal Transduction / genetics
Signal Transduction / immunology
Skin Diseases / genetics
Skin Diseases / immunology*
Skin Diseases / metabolism
Syk Kinase / genetics
Syk Kinase / immunology*
Syk Kinase / metabolism

Substances

Interleukin-1alpha
Myd88 protein, mouse
Myeloid Differentiation Factor 88
Receptors, Interleukin-1
Syk Kinase
Syk protein, mouse
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk1 protein, mouse
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7
Protein Tyrosine Phosphatase, Non-Receptor Type 6

Abstract

Publication types

MeSH terms

Substances

Grants and funding