Ets-2 deletion in myeloid cells attenuates IL-1α-mediated inflammatory disease caused by a Ptpn6 point mutation

The SHP-1 protein encoded by the Ptpn6 gene has been extensively studied in hematopoietic cells in the context of inflammation. A point mutation in this gene (Ptpn6^spin) causes spontaneous inflammation in mice, which has a striking similarity to neutrophilic dermatoses in humans. Recent findings highlighted the role of signaling adapters and kinases in promoting inflammation in Ptpn6^spin mice; however, the underlying transcriptional regulation is poorly understood. Here, we report that SYK is important for driving neutrophil infiltration and initiating wound healing responses in Ptpn6^spin mice. Moreover, we found that deletion of the transcription factor Ets2 in myeloid cells ameliorates cutaneous inflammatory disease in Ptpn6^spin mice through transcriptional regulation of its target inflammatory genes. Furthermore, Ets-2 drives IL-1α-mediated inflammatory signaling in neutrophils of Ptpn6^spin mice. Overall, in addition to its well-known role in driving inflammation in cancer, Ets-2 plays a major role in regulating IL-1α-driven Ptpn6^spin-mediated neutrophilic dermatoses. [Figure not available: see fulltext.].