期刊
JOURNAL OF IMMUNOLOGY
卷 201, 期 6, 页码 1639-1644出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1800760
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资金
- National Institutes of Health [CA163507, AR056296, AI124346, AI101935]
- American Lebanese Syrian Associated Charities
Mice homozygous for the Y208N amino acid substitution in the carboxy terminus of SHP-1 (referred to as Ptpn6(spin) mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6(spin) mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1 alpha and IL-1R signaling, we demonstrated a pivotal role for RIPK1, TAK1, and ASK1 in promoting inflammatory disease in Ptpn6(spin) mice. In the current study we have identified a previously unknown role for CARD9 signaling as a critical regulator for Ptpn6(spin) -mediated footpad inflammation. Genetic deletion of CARD9 significantly rescued the Ptpn6(spin)-mediated footpad inflammation. Mechanistically, enhanced IL-1 alpha-mediated signaling in Ptpn6(spin) mice neutrophils was dampened in Ptpn6(spin) Card9(-/-) mice. Collectively, this study identifies SHP-1 and CARD9 cross-talk as a novel regulator of IL-1 alpha-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.
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