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

08:00 EDT 19th March 2020 | BioPortfolio

Summary of "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) 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.

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Name: Cellular & molecular immunology
ISSN: 2042-0226
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Medical and Biotech [MESH] Definitions

Clonal hematopoetic disorder caused by an acquired genetic defect in PLURIPOTENT STEM CELLS. It starts in MYELOID CELLS of the bone marrow, invades the blood and then other organs. The condition progresses from a stable, more indolent, chronic phase (LEUKEMIA, MYELOID, CHRONIC PHASE) lasting up to 7 years, to an advanced phase composed of an accelerated phase (LEUKEMIA, MYELOID, ACCELERATED PHASE) and BLAST CRISIS.

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A mutation named with the blend of insertion and deletion. It refers to a length difference between two ALLELES where it is unknowable if the difference was originally caused by a SEQUENCE INSERTION or by a SEQUENCE DELETION. If the number of nucleotides in the insertion/deletion is not divisible by three, and it occurs in a protein coding region, it is also a FRAMESHIFT MUTATION.

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