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

Sarang Tartey; Prajwal Gurung; Rajendra Karki; Amanda Burton; Paul Hertzog; Thirumala-Devi Kanneganti

doi:10.1038/s41423-020-0398-7

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

Journal article

Open access

Peer reviewed

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

Sarang Tartey, Prajwal Gurung, Rajendra Karki, Amanda Burton, Paul Hertzog and Thirumala-Devi Kanneganti

Cellular & molecular immunology, Vol.18(7), pp.1798-1808

07/2021

DOI: 10.1038/s41423-020-0398-7

PMCID: PMC8245632

PMID: 32203187

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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 (Ptpn6 ) 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 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 mice. Moreover, we found that deletion of the transcription factor Ets2 in myeloid cells ameliorates cutaneous inflammatory disease in Ptpn6 mice through transcriptional regulation of its target inflammatory genes. Furthermore, Ets-2 drives IL-1α-mediated inflammatory signaling in neutrophils of Ptpn6 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 -mediated neutrophilic dermatoses. Model for the role of ETS-2 in neutrophilic inflammation in Ptpn6 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 Ptpn6 mice, the expression of these target genes is reduced, leading to the reduced pathology in neutrophilic dermatoses.

Animals

Inflammation - pathology

Interleukin-1alpha - metabolism

Mice

Neutrophils - metabolism

Point Mutation

Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics

Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism

Proto-Oncogene Protein c-ets-2 - genetics

Details

Title: Subtitle: Ets-2 deletion in myeloid cells attenuates IL-1α-mediated inflammatory disease caused by a Ptpn6 point mutation
Creators: Sarang Tartey - St. Jude Children's Research Hospital
Prajwal Gurung - University of Iowa
Rajendra Karki - St. Jude Children's Research Hospital
Amanda Burton - St. Jude Children's Research Hospital
Paul Hertzog - Hudson Institute of Medical Research
Thirumala-Devi Kanneganti - St. Jude Children's Research Hospital
Resource Type: Journal article
Publication Details: Cellular & molecular immunology, Vol.18(7), pp.1798-1808
DOI: 10.1038/s41423-020-0398-7
PMID: 32203187
PMCID: PMC8245632
ISSN: 1672-7681
eISSN: 2042-0226
Grant note: R01 AI101935 / NIAID NIH HHS R01 AR056296 / NIAMS NIH HHS K22 AI127836 / NIAID NIH HHS R37 AI101935 / NIAID NIH HHS R01 CA163507 / NCI NIH HHS R01 AI124346 / NIAID NIH HHS
Language: English
Date published: 07/2021
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984359793302771

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