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L. pneumophila pneumonia induces neutrophil recruitment to the lung through CXC chemokines. Previously, blocking CXCR2, the common receptor for CXC chemokines, but not CXCL1 or CXCL2, resulted in attenuated neutrophil accumulation and reduced survival following pulmonary L. pneumophila infection. However, gene-deficient mice were unavailable at that time and therefore, mechanisms of host protection and neutrophil homeostasis, including granulopoiesis and neutrophil release from the bone marrow, have not been investigated. Here, we delineated the role of CXCL1 and CXCL2 in host defense and neutrophil homeostasis using gene-deficient mice. Deficiency of CXCL1, but not CXCL2, impairs bacterial clearance and neutrophil accumulation in the lung. Furthermore, the increase of IL-18 and IFN-\u03b3 proteins in the lung caused by L. pneumophila infection is decreased in Cxcl1\u2212\/\u2212 mice. Moreover, this reduction in IFN-\u03b3 production in Cxcl1\u2212\/\u2212 mice is associated with a decrease in the \u03b3\u03b4TCR-expressing IFN-\u03b3+ subset. In vivo treatment with IL-18 or IFN-\u03b3 was found to restore neutrophil-dependent bacterial clearance in Cxcl1\u2212\/\u2212 mice. Production of CXCL1 not only by hematopoietic cells, but also by nonhematopoietic cells, is critical to augment host defense. In Cxcl1\u2212\/\u2212 mice, there is an impairment in emergency granulopoiesis in bone marrow and in neutrophil release to the blood. Also, Il-18\u2212\/\u2212 mice displayed impairment of neutrophil recruitment to the lung and bacterial clearance, neutrophil release, and emergency granulopoiesis. Collectively, CXCL1 derived from both hematopoietic and nonhematopoietic cells is essential to control L. pneumophila infection through the IL-18\u2013IFN-\u03b3 axis and neutrophil homeostasis.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf191","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T21:42:14Z","timestamp":1755034934000},"page":"3043-3054","source":"Crossref","is-referenced-by-count":1,"title":["CXCL1 augments host defense against\n                    <i>Legionella pneumophila<\/i>\n                    through the IL-18\u2013IFN-\u03b3 axis and neutrophil homeostasis"],"prefix":"10.1093","volume":"214","author":[{"given":"Ky V","family":"Hoang","sequence":"first","affiliation":[{"name":"Center for Lung Biology and Disease, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University and Agricultural & Mechanical College , Baton Rouge, LA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Le","sequence":"additional","affiliation":[{"name":"Center for Lung Biology and Disease, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University and Agricultural & Mechanical College , Baton Rouge, LA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Shan","sequence":"additional","affiliation":[{"name":"Center for Lung Biology and Disease, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University and Agricultural & Mechanical College , Baton Rouge, LA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1959-1328","authenticated-orcid":false,"given":"Samithamby","family":"Jeyaseelan","sequence":"additional","affiliation":[{"name":"Center for Lung Biology and Disease, Department of 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