Swiprosin-1 deficiency impairs macrophage immune response of septic mice
Su Zhang, Ye Tu, Yi-Ming Sun, Ya Li, Rong-Mei Wang, Yongbing Cao, Ling Li, Li-Chao Zhang, Zhi-Bin Wang
Su Zhang, Ye Tu, Yi-Ming Sun, Ya Li, Rong-Mei Wang, Yongbing Cao, Ling Li, Li-Chao Zhang, Zhi-Bin Wang
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Research Article Immunology Infectious disease

Swiprosin-1 deficiency impairs macrophage immune response of septic mice

Abstract

Despite the fact that many therapeutic strategies have been adopted to delay the development of sepsis, sepsis remains one of the leading causes of death in noncoronary intensive care units. Recently, sepsis-3 was defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Here, we report that swiprosin-1 (also known as EFhd2) plays an important role in the macrophage immune response to LPS-induced or cecal ligation and puncture–induced (CLP-induced) sepsis in mice. Swiprosin-1 depletion causes higher mortality, more severe organ dysfunction, restrained macrophage recruitment in the lung and kidney, and attenuated inflammatory cytokine production (including IL-1β, IL-6, TNF-α, IL-10, and IFN-γ). The immunosuppression caused by swiprosin-1 deficiency is manifested by impaired bactericidal capacity and decreased HLA-DR expression in macrophages. Swiprosin-1 affects the activation of the JAK2/STAT1/STAT3 pathway by regulating the expression of IFN-γ receptors in macrophages. Our findings provide a potential target for the regulation of the macrophage immune response in sepsis.

Authors

Su Zhang, Ye Tu, Yi-Ming Sun, Ya Li, Rong-Mei Wang, Yongbing Cao, Ling Li, Li-Chao Zhang, Zhi-Bin Wang

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Figure 1

Swiprosin-1–KO mice exhibited higher mortality and immunosuppression after LPS- and CLP-induced sepsis.

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Swiprosin-1–KO mice exhibited higher mortality and immunosuppression aft...
(A) Survival curves after i.p. LPS (40 mg/kg) (n = 11, *P < 0.05, WT vs. KO), Log-rank (Mantel-Cox). (B) The levels of IL-1β, IL-6, and TNF-α in the serum after i.p. LPS for 6 hours (n = 6–8, ***P < 0.001, WT control (WT-CON) vs. WT-LPS; #P < 0.05, ###P < 0.001, KO-CON vs. KO-LPS; ┼P < 0.05, ┼┼┼P < 0.001, WT-LPS vs. KO-LPS), 1-way ANOVA (LSD test) ; the results are depicted as the mean ± SEM. (C) Survival curves after cecal ligation and puncture (CLP) treatment (n = 10, *P < 0.05, WT vs. KO), Log-rank (Mantel-Cox). (D) The levels of IL-6 and TNF-α in the serum after CLP treatment for 18 hours (n = 7 or 8, ***P < 0.001, WT-Sham vs. WT-CLP; ┼P < 0.05, ┼┼┼P < 0.001, WT-CLP vs. KO-CLP), 1-way ANOVA (LSD test); the results are depicted as the mean ± SEM. (E) IL-10 concentration in the serum after i.p. LPS for 6 hours (n = 8, ┼┼┼P < 0.05, WT-LPS vs. KO-LPS), 1-way ANOVA (LSD test); the results are depicted as the mean ± SEM. (F) Survival curves after supplementing with WT and KO macrophages in the macrophage-depleted mice after i.p. LPS (n = 6, *P < 0.05, WT-Mφ vs. KO-Mφ), Log-rank (Mantel-Cox). (G) Bacterial burden in the blood of the LPS-induced septic mice (n = 3, ***P < 0.001, WT vs. KO), 2-tailed t test; the results are depicted as the mean ± SEM. (H) Bacterial burden in the blood and peritoneal lavage fluid of the CLP-induced septic mice (n = 3, **P < 0.01, ***P < 0.001, WT vs. KO), 2-tailed t test; the results are depicted as the mean ± SEM.