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Background: Dendritic cell (DC) dysfunction plays a central role in sepsis-induced immunosuppression. Recent research has indicated that collective mitochondrial fragmentation contributes to the dysfunction of immune cells observed during sepsis. PTEN-induced putative kinase 1 (PINK1) has been characterized as a guide for impaired mitochondria that can keep mitochondrial homeostasis. However, its role in the function of DCs during sepsis and the related mechanisms remain obscure. In our study, we elucidated the effect of PINK1 on DC function during sepsis and its underlying mechanism of action. Methods: Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) treatment were used as in vivo and in vitro sepsis models, respectively. Results: We found that changes in mitochondrial PINK1 expression of DCs paralleled changes in DC function during sepsis. The ratio of DCs expressing MHC-II, CD86, and CD80, the mRNAs level of dendritic cells expressing TNF-α and IL-12, and the level of DC-mediated T-cell proliferation were all decreased, both in vivo and in vitro during sepsis, when PINK1 was knocked out. This suggested that PINK1 knockout prevented the function of DCs during sepsis. Furthermore, PINK1 knockout inhibited Parkin RBR E3 ubiquitin protein (Parkin)-dependent mitophagy and enhanced dynamin-related protein 1 (Drp1)-related mitochondrial fission, and the negative effects of PINK1 knockout on DC function following LPS treatment were reversed by Parkin activation and Drp1 inhibitor. Knockout of PINK1 also increased apoptosis of DCs and the mortality of CLP mice. Conclusion: Our results indicated that PINK1 protected against DC dysfunction during sepsis through the regulation of mitochondrial quality control.

Vascular endothelial functional dysregulation and barrier disruption are involved the initiation and development of sepsis. Growth arrest-specific protein 6 (Gas6), one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), is confirmed to have beneficial functions in hemostasis, inflammation, and cancer growth. Here, we demonstrated the protective effects of Gas6 on multi-organ dysfunction syndrome (MODS) in sepsis and the underlying mechanisms. We investigated Gas6-ameliorated MODS by inhibiting vascular endothelial hyperpermeability in a mouse model of sepsis. Additionally, in vitro, under lipopolysaccharide (LPS) stimulation in vascular endothelial cells, Gas6 attenuated vascular endothelial hyperpermeability by reinforcing the tight junction proteins occludin, zonula occludens-1 (ZO-1), and claudin5. Furthermore, Gas6 substantially suppressed NF-κB p65 activation. In addition, blocking the Gas6 receptor, Axl, partially reduced the protective effect of Gas6 on the vascular endothelial barrier and diminished the inhibitive effect of Gas6 on NF-κB p65 activation. Taken together, this study suggests that Gas6 has a protective effect on MODS in sepsis by inhibiting the vascular endothelial hyperpermeability and alteration of tight junction and that the Axl/NF-κB signaling pathway underlies these effects.

Apoptosis of CD4⁺ T cells plays a central role in the progression of sepsis because it is associated with subsequent immunosuppression and the lack of specific treatment. Thus, developing therapeutic strategies to attenuate the apoptosis of CD4⁺ T cells in sepsis is critical. Several studies have demonstrated that Mdivi-1, which is a selective inhibitor of the dynamin-related protein 1 (Drp1), attenuates apoptosis of myocardial cells and neurons during various pathologic states. The present study revealed the impact of Mdivi-1 on the apoptosis of CD4⁺ T cells in sepsis and the potential underlying mechanisms. We used lipopolysaccharide (LPS) stimulation and cecal ligation and puncture (CLP) surgery as sepsis models in vitro and in vivo, respectively. Our results showed that Mdivi-1 attenuated the apoptosis of CD4⁺ T cells both in vitro and in vivo. The potential mechanism underlying the protective effect of Mdivi-1 involved Mdivi-1 reestablishing mitochondrial fusion-fission balance in sepsis, as reflected by the expression of the mitofusin 2 (MFN2) and optic atrophy 1 (OPA1) , Drp1 translocation, and mitochondrial morphology, as observed by electron microscopy. Moreover, Mdivi-1 treatment reduced reactive oxygen species (ROS) production and prevented the induction of endoplasmic reticulum stress (ERS) and associated apoptosis. After using tunicamycin to activate ER stress, the protective effect of Mdivi-1 on CD4⁺ T cells was reversed. Our results suggested that Mdivi-1 ameliorated apoptosis in CD4⁺ T cells by reestablishing mitochondrial fusion-fission balance and preventing the induction of endoplasmic reticulum stress in experimental sepsis.