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

Abstract

SUMMARY 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 (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.

Function and regulation of IL‐1α in inflammatory diseases and cancer

“…Recent reports show that perinatal death of RIPK1‐deficient mice can be rescued by simultaneous deletion of both RIPK3 and caspase‐8 . In line with a critical role for RIPK1 in inducing disease in these mice, simultaneous germline deletion of caspase‐8, RIPK3, and RIPK1, but not RIPK3 and/or caspase‐8, protects Ptpn6 spin mice from disease . These studies demonstrate that IL‐1α production from non‐hematopoietic cells and scaffolding activity of RIPK1 is required for disease development in Ptpn6 spin mice, whereas RIPK3 and MLKL‐mediated necroptosis is dispensable.…”

“…Transgenic mice that overexpress IL‐1α in epidermal cells also develop an inflammatory skin disease, underscoring the pathogenic role of excess IL‐1α production in skin inflammation . Bone marrow chimera studies further reveal that while Ptpn6 spin mutation in hematopoietic cells is required for disease development in these mice, the non‐hematopoietic cells are the primary source of pathogenic IL‐1α . Microabrasion injury in the footpads also accelerates disease progression and enhances severity in prediseased Ptpn6 spin mice, suggesting that passive release of IL‐1α from epidermal cells during necrotic cell death is an instigator of disease .…”

“…MLKL is a pseudokinase that forms pores in the plasma membrane, leading to loss of osmolarity, and eventual death of the cell . Ptpn6 spin mice that are also genetically deficient in RIPK3, MLKL, or RIPK1 kinase activity develop the disease with the same severity as the Ptpn6 spin mice . While RIPK1‐deficient mice die perinatally, fetal liver chimeras with Ptpn6 spin and RIPK1‐deficient bone marrow donor cells are protected from disease development .…”

“…Microabrasion injury in the footpads also accelerates disease progression and enhances severity in prediseased Ptpn6 spin mice, suggesting that passive release of IL‐1α from epidermal cells during necrotic cell death is an instigator of disease . Microabrasion in the footpads of WT mice also leads to enhanced TNF‐α, G‐CSF, and KC production in an IL‐1α‐dependent manner . However, production of IL‐1α, as well as G‐CSF and KC is unaffected in the microabrated footpads of TNF‐α ‐ deficient mice .…”

“…Microabrasion in the footpads of WT mice also leads to enhanced TNF‐α, G‐CSF, and KC production in an IL‐1α‐dependent manner . However, production of IL‐1α, as well as G‐CSF and KC is unaffected in the microabrated footpads of TNF‐α ‐ deficient mice . Furthermore, genetic deletion of TNF‐α or TNFR adaptor tumor necrosis factor receptor type 1‐associated death domain protein (TRADD) in Ptpn6 spin mice only partially protects mice from the disease .…”