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This study investigated the involvement of IFNLR1+ monocytes\/macrophages in orchestrating pro-fibrotic immune microenvironment. Flow cytometric analysis of peripheral blood showed that IFNLR1+ monocytes were elevated in patients with chronic hepatitis B virus (HBV) infection (CHI) and patients with HBV-related liver cirrhosis (LC), compared with healthy controls (HC). These cells also displayed a CCR2hiCCR5hiCX3CR1hiCD86hiHLA-DRhiCD163hiMERTKhi phenotype with an IL-10hiTNF-\u03b1hi cytokine profile. Hepatic fibrosis was induced in wild-type and Ifnlr1-knockout (Ifnlr1\u2212\/\u2212) mice using carbon tetrachloride and recombinant adeno-associated virus 8-1.3HBV. Ifnlr1 deficiency down-regulated CCR2 and CCR5 expression on monocytes\/macrophages, attenuated collagen deposition, but enhanced HBV\u2013DNA replication. In vitro, bone marrow-derived macrophages (BMDMs) were co-cultured with hepatic stellate cells (HSCs) or naive CD4+ T cells to assess the functional impact of IFNLR1+ macrophages. Concurrently, the involvement of lipid metabolism in IFN-\u03bb\/IFNLR1-mediated macrophage regulation was examined using liver X receptor (LXR) agonists\/antagonists. Ifnlr1\u2212\/\u2212 BMDMs exhibited a diminished capacity to activate HSCs and drive regulatory T cells differentiation. Mechanistically, IFN-\u03bb\u2013IFNLR1 signaling suppressed LXR-dependent lipid metabolism, thereby promoting tumor necrosis factor (TNF)-\u03b1 and IL-1\u03b2 production, and LXR pathway inhibition favored M1-macrophage polarization. Collectively, IFNLR1 identifies a pro-fibrotic and immunoregulatory monocyte\/macrophage subset. Targeting IFNLR1\u2013LXR axis may represent promising anti-fibrotic strategies for HBV-related liver fibrosis.<\/jats:p>","DOI":"10.1042\/cs20261452","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:38:45Z","timestamp":1789472325000},"page":"2229-2247","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interferon-\u03bb receptor positive monocytes\/macrophages orchestrate a pro-fibrotic immune environment in hepatitis B virus-related liver fibrosis"],"prefix":"10.1042","volume":"140","author":[{"given":"Siqi","family":"Wang","sequence":"first","affiliation":[{"name":"1Department of Allergy, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"2Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqin","family":"Li","sequence":"additional","affiliation":[{"name":"3Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, China"},{"name":"4Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"3Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zicheng","family":"Liu","sequence":"additional","affiliation":[{"name":"4Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucheng","family":"Zhu","sequence":"additional","affiliation":[{"name":"3Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisha","family":"Cheng","sequence":"additional","affiliation":[{"name":"5Department of Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyuan","family":"Chen","sequence":"additional","affiliation":[{"name":"4Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Shen","sequence":"additional","affiliation":[{"name":"4Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wu","sequence":"additional","affiliation":[{"name":"4Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"6Department of Medical Microbiology and Parasitology, MOE\/NHC\/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai 200032, China"},{"name":"7Shanghai Institute of Liver Disease, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9354-6699","authenticated-orcid":false,"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[{"name":"3Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen 361015, China"},{"name":"4Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"7Shanghai Institute of Liver Disease, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"2026100106511010300_B1","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1146\/annurev-immunol-083024-032807","article-title":"Molecular, cellular, tissue, and organismal functions of type III interferons","volume":"44","author":"Boehmer","year":"2026","journal-title":"Annu. 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