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Pharmacokinetic studies were performed in Fas<jats:sup><jats:italic>lpr<\/jats:italic><\/jats:sup> mice and healthy Institute of Cancer Research mice. Efficacy of CXCL5 administration was demonstrated in Fas<jats:sup><jats:italic>lpr<\/jats:italic><\/jats:sup> mice, and the working mechanism of CXCL5 treatment was elucidated by flow cytometry, Luminex, and RNA sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In SLE patients, serum CXCL5 levels were significantly lower than in healthy individuals (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001) and negatively correlated with disease activity (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.004). In Fas<jats:sup><jats:italic>lpr<\/jats:italic><\/jats:sup> mice, disease severity progressed with age and was negatively associated with plasma CXCL5 levels. Intravenous administration of CXCL5 to Fas<jats:sup><jats:italic>lpr<\/jats:italic><\/jats:sup> mice restored endogenous circulatory CXCL5, improved mice survival, and reduced anti\u2013double\u2010stranded DNA antibodies, proteinuria, lupus nephritis activity and chronicity indices, renal complements, and neutrophil extracellular traps over short\u2010term (10\u2009weeks) and long\u2010term (2\u2009years) time periods. In vitro and in vivo assays demonstrated that CXCL5 dictated neutrophil trafficking and suppressed neutrophil activation, degranulation, proliferation, and renal infiltration. Renal and splenic RNA sequencing further showed that CXCL5\u2010mediated immunomodulation occurred by promoting energy production in renal\u2010infiltrated immune cells, activating certain T cells, and reducing tissue fibrosis, granulocyte extravasation, complement components, and interferons. Further factorial design results indicated that CXCL5 appears to enhance host tolerability to cyclophosphamide in vulnerable individuals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We found that serum CXCL5 levels were significantly lower in SLE patients than in healthy individuals and were negatively correlated with disease activity. By administering CXCL5 intravenously in a mouse model of lupus, mouse survival improved, and indices of disease activity reduced significantly. Taken together, these findings indicate CXCL5 administration may represent a novel myeloid\/neutrophil\u2010targeting therapy for SLE.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42383","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T13:09:22Z","timestamp":1665752962000},"page":"553-566","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Dampened Inflammation and Improved Survival After CXCL5 Administration in Murine Lupus via Myeloid and Neutrophil Pathways"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9479-6913","authenticated-orcid":false,"given":"Xiubo","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Clinical Translational Research Singapore General Hospital, and SingHealth Duke\u2010NUS Medicine Academic Clinical Programme, Duke\u2010NUS Medical School  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6396-1701","authenticated-orcid":false,"given":"Chin Teck","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology Singapore General Hospital, and SingHealth Duke\u2010NUS Medicine Academic Clinical Programme, Duke\u2010NUS Medical School  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianyang","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Clinical Translational Research Singapore General Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Clinical Translational Research Singapore General Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia Chi","family":"Tan","sequence":"additional","affiliation":[{"name":"Single\u2010cell Computational Immunology Singapore Immunology Network  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Law","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology Singapore General Hospital  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lim Hee","family":"Goh","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology Singapore General Hospital  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi Yong","family":"Poon","sequence":"additional","affiliation":[{"name":"Department of Clinical Translational Research Singapore General Hospital, and Critical Analytics for Manufacturing Personalized Medicine, SMART  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Hematology Singapore General Hospital, and SingHealth Duke\u2010NUS Medicine Academic Clinical Programme, Duke\u2010NUS Medical School  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Say Li","family":"Kong","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore  Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Clinical Translational Research Singapore General Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang","family":"Li","sequence":"additional","affiliation":[{"name":"Cancer &amp; 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