Abstract

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 (Ptpn6spin) 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 Ptpn6spin 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 Ptpn6spin mice. Moreover, we found that deletion of the transcription factor Ets2 in myeloid cells ameliorates cutaneous inflammatory disease in Ptpn6spin mice through transcriptional regulation of its target inflammatory genes. Furthermore, Ets-2 drives IL-1α-mediated inflammatory signaling in neutrophils of Ptpn6spin 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 Ptpn6spin-mediated neutrophilic dermatoses. Model for the role of ETS-2 in neutrophilic inflammation in Ptpn6spin mice. Mutation of the Ptpn6 gene results in SYK phosphorylation which then sequentially activates MAPK signaling pathways and activation of ETS-2. This leads to activation of ETS-2 target genes that contribute to neutrophil migration and inflammation. When Ets2 is deleted in Ptpn6spin mice, the expression of these target genes is reduced, leading to the reduced pathology in neutrophilic dermatoses.

Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.