Immunobiology · 2026
rFgl2-treated CD32b+M2 macrophages effectively inhibits cardiac transplant rejection in mice.
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Ji Wenbin, Zhang Baotong, Zhang Jiansheng, Chen Guoshan, Wang Weiwei, Qi Feng
Аннотация
BACKGROUND: The search for additional therapies against acute rejection is warranted. Alternatively activated macrophages (M2 macrophages) have immunomodulatory functions, and enhancement of their immunomodulatory capacity is a feasible complementary therapy. Fcγ receptor II b (FcγRIIb, CD32b), which is highly expressed by M2 macrophages, and its important ligand, fibrinogen-like protein 2 (Fgl2), are immunosuppressive molecules, and it is necessary to explore the potential of both to enhance the immunomodulatory capacity of M2 macrophages.
METHODS: In vitro, CD32b+M2 macrophages obtained by magnetic bead sorting were treated with recombinant Fgl2 (rFgl2) to explore their immunomodulatory capacity under simulated inflammatory (lipopolysaccharide+interferon γ) stimuli and the possible mechanisms using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and western blotting (WB), and they were co-cultured with CD4+T cells to explore their modulation of the polarization of regulatory T cells (Tregs). In vivo, rFgl2-treated CD32b+M2 macrophages were used to treat abdominal heart transplantation model mice, and systemic inflammation, changes in systemic proportions of macrophages, CD4+, CD8+T cells, and Tregs, and infiltration in grafts were examined using ELISA, hematoxylin-eosin staining, immunohistochemistry, and flow cytometry.
RESULTS: In vitro CD32b+M2 macrophages treated with rFgl2 further expressed IL-10 and TGF-β1 and had increased levels of phosphorylation of SHP2 and STAT3, which effectively increased the proportion of Tregs after co-culture with CD4+T cells. In vivo rFgl2-treated CD32b+M2 macrophages increased the proportion of M2 macrophages and Tregs, improved systemic inflammation, attenuated graft injury, reduced inflammatory cell infiltration, and prolonged graft survival.
CONCLUSIONS: rFgl2 promotes the differentiation of Tregs by activating SHP2 and thus promoting STAT3 activation, which in turn promotes the secretion of the inflammation-suppressing cytokine IL-10 as well as TGF-β1. rFgl2-treated CD32b+M2 macrophages alleviate the acute rejection of cardiac transplants in mice by promoting differentiation of M2 macrophages as well as Tregs, which can be used as a complementary treatment to reduce the adverse effects of immunosuppression and prolong the survival time of allogeneic transplants.
METHODS: In vitro, CD32b+M2 macrophages obtained by magnetic bead sorting were treated with recombinant Fgl2 (rFgl2) to explore their immunomodulatory capacity under simulated inflammatory (lipopolysaccharide+interferon γ) stimuli and the possible mechanisms using enzyme-linked immunosorbent assay (ELISA), flow cytometry, and western blotting (WB), and they were co-cultured with CD4+T cells to explore their modulation of the polarization of regulatory T cells (Tregs). In vivo, rFgl2-treated CD32b+M2 macrophages were used to treat abdominal heart transplantation model mice, and systemic inflammation, changes in systemic proportions of macrophages, CD4+, CD8+T cells, and Tregs, and infiltration in grafts were examined using ELISA, hematoxylin-eosin staining, immunohistochemistry, and flow cytometry.
RESULTS: In vitro CD32b+M2 macrophages treated with rFgl2 further expressed IL-10 and TGF-β1 and had increased levels of phosphorylation of SHP2 and STAT3, which effectively increased the proportion of Tregs after co-culture with CD4+T cells. In vivo rFgl2-treated CD32b+M2 macrophages increased the proportion of M2 macrophages and Tregs, improved systemic inflammation, attenuated graft injury, reduced inflammatory cell infiltration, and prolonged graft survival.
CONCLUSIONS: rFgl2 promotes the differentiation of Tregs by activating SHP2 and thus promoting STAT3 activation, which in turn promotes the secretion of the inflammation-suppressing cytokine IL-10 as well as TGF-β1. rFgl2-treated CD32b+M2 macrophages alleviate the acute rejection of cardiac transplants in mice by promoting differentiation of M2 macrophages as well as Tregs, which can be used as a complementary treatment to reduce the adverse effects of immunosuppression and prolong the survival time of allogeneic transplants.