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However, the mechanisms underlying this outstanding pathology remain incompletely understood. Here, we report that CFTR in myeloid immune cells plays a pivotal role in control of neutrophilic inflammation. Myeloid CFTR-Knockout (Mye-Cftr\u2212\/\u2212) mice and congenic wild-type (WT) mice were challenged peritoneally with zymosan particles at different doses, creating aseptic peritonitis with varied severity. A high-dose challenge resulted in significantly higher mortality in Mye-Cftr\u2212\/\u2212 mice, indicating an intrinsic defect in host control of inflammation in mice whose myeloid cells lack CF. The low-dose challenge demonstrated an impaired resolution of inflammation in Mye-Cftr\u2212\/\u2212 mice, reflected by a significant overproduction of proinflammatory cytokines, including neutrophil chemokines MIP-2 and KC, and sustained accumulation of neutrophils. Tracing neutrophil mobilization in vivo demonstrated that myeloid CF mice recruited significantly more neutrophils than did WT mice. Pulmonary challenge with zymosan elicited exuberant inflammation in the lung and recapitulated the findings from peritoneal challenge. To determine the major type of cell that was primarily responsible for the over-recruitment of neutrophils, we purified and cultured ex vivo zymosan-elicited peritoneal neutrophils and macrophages. The CF neutrophils produced significantly more MIP-2 than did the WT counterparts, and peripheral blood neutrophils isolated from myeloid CF mice also produced significantly more MIP-2 after zymosan stimulation in vitro. These data altogether suggest that CFTR dysfunction in myeloid immune cells, especially neutrophils, leads to hyperinflammation and excessive neutrophil mobilization in the absence of infection. Thus, dysregulated inflammation secondary to abnormal or absent CFTR in myeloid cells may underlie the clinically observed neutrophilic inflammation in CF.<\/jats:p>","DOI":"10.1002\/jlb.3a0520-193rr","type":"journal-article","created":{"date-parts":[[2020,6,12]],"date-time":"2020-06-12T23:55:30Z","timestamp":1592006130000},"page":"1777-1785","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Myeloid CFTR loss-of-function causes persistent neutrophilic inflammation in cystic fibrosis"],"prefix":"10.1093","volume":"108","author":[{"given":"Hang Pong","family":"Ng","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center , New Orleans, Louisiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Jennings","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center , New Orleans, Louisiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianne","family":"Wellems","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center , New Orleans, Louisiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physiology, Wayne State University School of Medicine , Detroit, Michigan , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School , Ann Arbor, Michigan , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M","family":"Nauseef","sequence":"additional","affiliation":[{"name":"Department of Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, and Veterans Administration Medical Center , Iowa City, Iowa , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4057-1399","authenticated-orcid":true,"given":"Guoshun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center , New Orleans, Louisiana , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,6,12]]},"reference":[{"key":"2023032108063518400_jlb10687-cit-0001","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1126\/science.256.5058.774","article-title":"Cystic fibrosis: molecular biology and therapeutic 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