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However, the detailed mechanism of the neutrophil function in psoriasis progression remains unclear. Here, we found that both Src homology\u20102 domain\u2010containing protein tyrosine phosphatase\u20102 (SHP2) and neutrophils were highly correlated to developing psoriasis by single\u2010cell ribonucleic acid (RNA) sequencing and experiment verification. The deficiency of SHP2 in neutrophils significantly alleviated psoriasis\u2010like phenotype in an imiquimod\u2010induced murine model. Interestingly, high levels of neutrophil extracellular traps (NETs) were produced in the inflamed lesions of psoriatic patients. In addition, imiquimod\u2010induced psoriasis\u2010like symptoms were remarkably ameliorated in peptidyl arginine deiminase 4 (PAD4) knockout mice, which cannot form NETs. Mechanistically, RNA\u2010seq analysis revealed that SHP2 promoted the formation of NETs in neutrophils via the ERK5 pathway. Functionally, this mechanism resulted in the infiltration of pro\u2010inflammatory cytokines such as TNF\u2010<jats:italic>\u03b1<\/jats:italic>, IL\u20101<jats:italic>\u03b2<\/jats:italic>, IL\u20106, IL\u201017A, and CXCL\u201015, which enhances the inflammatory response in skin lesions and reinforces the cross\u2010talk between neutrophils and keratinocytes, ultimately aggravating psoriasis. Our findings uncover a role for SHP2 in NET release and subsequent cell death known as NETosis in the progression of psoriasis and suggest that SHP2 may be a promising therapeutic target for psoriasis.<\/jats:p>","DOI":"10.1002\/mco2.120","type":"journal-article","created":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T05:23:56Z","timestamp":1646457836000},"source":"Crossref","is-referenced-by-count":39,"title":["Tyrosine phosphatase SHP2 exacerbates psoriasis\u2010like skin inflammation in mice via ERK5\u2010dependent NETosis"],"prefix":"10.1002","volume":"3","author":[{"given":"Yan","family":"Ding","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijun","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Institute of Marine Biomedicine, 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