Novel Role of Endothelial Derived Exosomal HSPA12B in Regulating Macrophage Inflammatory Responses in Polymicrobial Sepsis

Abstract

Endothelial cell dysfunction contributes to sepsis induced initiate immune response and the infiltration of immune cells into organs, resulting in organ injury. Heat shock protein A12B (HSPA12B) is predominantly expressed in endothelial cells. The present study investigated whether endothelial HSPA12B could regulate macrophage proinflammatory response during sepsis. Wild type (WT) and endothelial cell-specific HSPA12B deficient (HSPA12B −/− ) mice were subjected to CLP sepsis. Mortality and cardiac function were monitored. Higher mortality, worsened cardiac dysfunction, and greater infiltrated macrophages in the myocardium and spleen were observed in HSPA12B −/− septic mice compared with the WT septic mice. The serum levels of TNFα and IL-1β were higher and the levels of IL-10 were lower in HSPA12B −/− septic mice than in WT septic mice. Importantly, endothelial exosomes contain HSPA12B which can be uptaken by macrophages. Interestingly, endothelial exosomal HSPA12B significantly increases IL-10 levels and decreases TNF-α and IL-1β production in LPS-stimulated macrophages. Mechanistic studies show that endothelial exosomal HSPA12B downregulates NF-κB activation and nuclear translocation in LPS stimulated macrophages. These data suggest that endothelial HSPA12B plays a novel role in the regulation of macrophage pro-inflammatory response via exosomes during sepsis and that sepsis induced cardiomyopathy and mortality are associated with endothelial cell deficiency of HSPA12B.

Exosome: The Regulator of the Immune System in Sepsis

“…Heat shock protein A12B (HSPA12B) is mainly expressed in endothelial cells and transferred from released exosomes to macrophages ( Figure 5 ). By inhibiting the activation and nuclear translocation of NF-kB, it significantly increases the IL-10 level of LPS-stimulated macrophages and reduces the production of TNF-α and IL-1β ( Tu et al, 2020 ). In addition, HSPA12B reduces the expression of LPS-induced adhesion molecules and the production of pro-inflammatory cytokines via activating the PI3K/Akt signaling pathway of target cells ( Li et al, 2013 ), which contribute to reduce the migration and adhesion of macrophages to target cells in sepsis ( Tu et al, 2020 ).…”

“…By inhibiting the activation and nuclear translocation of NF-kB, it significantly increases the IL-10 level of LPS-stimulated macrophages and reduces the production of TNF-α and IL-1β ( Tu et al, 2020 ). In addition, HSPA12B reduces the expression of LPS-induced adhesion molecules and the production of pro-inflammatory cytokines via activating the PI3K/Akt signaling pathway of target cells ( Li et al, 2013 ), which contribute to reduce the migration and adhesion of macrophages to target cells in sepsis ( Tu et al, 2020 ). Endothelial microparticles (EMP) has been shown to promote the maturation of plasma cell-derived dendritic cell (PDC) by up-regulating the expression of costimulatory molecules and promoting the release of IL-6 and IL-8 ( Angelot et al, 2009 ).…”

“…Heat shock protein A12B (HSPA12B) is mainly expressed in endothelial cells and transferred from released exosomes to macrophages (Figure 5). By inhibiting the activation and nuclear translocation of NF-kB, it significantly increases the IL-10 level of LPS-stimulated macrophages and reduces the production of TNF-α and IL-1β (Tu et al, 2020). In addition, FIGURE 5 | Role of exosomes derived from epithelial and endothelial cells in sepsis.…”

Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment

“…[178] Additionally, when heat shock protein A12B (HSPA12B), which is predominantly expressed in the endothelium and upregulates miR-126, was loaded into HU-VEC EVs via adenovirus-mediated overexpression, the EVs suppressed LPS-induced inflammatory cytokine secretion in murine macrophages via the downregulation of NF-B. [179] Finally, additional cell types have been investigated due to their established utility in biotechnological processes, increasing translational potential. Notably, Choi et al recently reported the development of human embryonic kidney 293T (HEK293T) EV-based delivery of super-repressor I(kappa)B (I B) to reduce sepsis-associated organ damage and mortality.…”

“…[ 178 ] Additionally, when heat shock protein A12B (HSPA12B), which is predominantly expressed in the endothelium and upregulates miR‐126, was loaded into HUVEC EVs via adenovirus‐mediated overexpression, the EVs suppressed LPS‐induced inflammatory cytokine secretion in murine macrophages via the downregulation of NF‐κB. [ 179 ]…”