title: IFN-γ differentially regulates subsets of Gr-1(+)CD11b(+) myeloid cells in chronic inflammation.
abstract: During chronic inflammation, prolonged over-reactive immune response may lead to tissue destruction, while immune suppression hinders tissue repair and pathogen elimination. Therefore, precise regulation of the immune response is needed to avoid immuno-pathology. Interferon-gamma (IFN-γ) is widely used in clinical treatment of inflammatory diseases. However, the underlying mechanism remains unclear. Here, we evaluated the role of IFN-γ on CD11b(+)Gr-1(+) myeloid cell differentiation and function, using a heat-killed Mycobacterium bovis BCG-induced chronic inflammation model. After challenge with heat-killed BCG, two subpopulations of CD11b(+)Gr-1(+) myeloid cells were generated in the mouse spleen. Phenotypical, morphological and functional analysis indicated that the CD11b(+)Gr-1(high) Ly6G(high) Ly6C(low) subset was neutrophil-like myeloid-derived inducer cells (N-MDICs), which promoted T cell activation, while the other subset was CD11b(+)Gr-1(low) Ly6G(neg) Ly6C(high) monocyte-like myeloid-derived suppressor cells (M-MDSCs) that displayed extensive suppressor function. IFN-γ treatment dampened N-MDICs-mediated T cell activation through up-regulating T cell suppressive mediators, reactive oxygen species (ROS) and arginase I. While for M-MDSCs, IFN-γ reduced their suppressing activity by decreasing the arginase activity. Our study provides evidence that IFN-γ balances the over-reactive vs compromised immune response through different regulation of distinct myeloid subsets, and therefore displays significant therapeutic potential for effective immuno-therapy of chronic inflammatory diseases.
authors.affiliation: Department of Immunology, Institute of Tuberculosis Control, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Guangzhou Chest Hospital, Guangzhou 510095, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Immunology, Institute of Tuberculosis Control, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Shengfeng
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Immunology, Institute of Tuberculosis Control, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Immunology, Institute of Tuberculosis Control, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.affiliation: Guangzhou Chest Hospital, Guangzhou 510095, China.
authors.forename: Chunxin
authors.initials: C
authors.lastname: Liao
authors.affiliation: Houston Methodist Hospital Research Institute, Houston 77030, TX, USA.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Institute of Tuberculosis Control, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Immunology, Institute of Tuberculosis Control, Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China; Houston Methodist Hospital Research Institute, Houston 77030, TX, USA. Electronic address: wuminhao@mail.sysu.edu.cn.
authors.forename: Minhao
authors.initials: M
authors.lastname: Wu
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000276:immunology; D001119:Arginase / Q000235:genetics / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D002908:Chronic Disease; D005260:Female; D005786:Gene Expression Regulation; D006358:Hot Temperature; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D009163:Mycobacterium bovis / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000276:immunology; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; C480309:Ly6G antigen, mouse; D017382:Reactive Oxygen Species; D019707:Receptors, Chemokine; D007371:Interferon-gamma; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: Chronic inflammation; IFN-γ; Myeloid-derived suppressor cells; Neutrophil-like myeloid-derived inducer cells