Cutting Edge: Dysregulated CARD9 Signaling in Neutrophils Drives Inflammation in a Mouse Model of Neutrophilic Dermatoses [CUTTING EDGE]

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-1α 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-1α–mediated signaling in Ptpn6^spin mice neutrophils was dampened in Ptpn6^spinCard9^–/– mice. Collectively, this study identifies SHP-1 and CARD9 cross-talk as a novel regulator of IL-1α–driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.

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