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Cell Mol Immunol. 2020 Mar 19. doi: 10.1038/s41423-020-0398-7. [Epub ahead of print]

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

Author information

1
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
2
Inflammation Program, University of Iowa, Iowa City, IA, 52241, USA.
3
Centre for Innate Immunity & Infectious Diseases, Hudson Institute of Medical Research, Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, 3168, Australia.
4
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Thirumala-Devi.Kanneganti@StJude.org.

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.

KEYWORDS:

Autoinflammation; ETS-2; IL-1α; Neutrophilic dermatoses; PTPN6; SHP-1

PMID:
32203187
DOI:
10.1038/s41423-020-0398-7

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