Abstract
PurposeEndogenously produced glucocorticoids exhibit immunomodulating properties and are of pivotal importance for sepsis outcome. Uncontrolled activation of the immune-adrenal crosstalk increases the risk of sepsis-related death. Triggering receptor expressed on myeloid cells-2 (TREM2) is richly expressed on macrophages and has been demonstrated to improve outcome of sepsis by enhancing elimination of pathogens. However, the role and mode of action of macrophage TREM2 on adrenocortical steroidogenesis remains unclear in septic shock. MethodsThe acute septic shock model was established by intraperitoneally challenging wild-type (WT) and TREM2 knock-out (Trem2−/−) mice with lipopolysaccharide (LPS, 30 mg/kg). The mice were assessed for TREM2 expression and local inflammation in adrenal gland and for synthesis of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in vivo. Bone marrow-derived macrophages or macrophage-derived exosomes were isolated from WT and Trem2−/− mice and were co-cultured with adrenocortical cells. The expression of steroidogenic enzymes and corticosterone production was assessed. ResultsGenetic deficiency of TREM2 caused significantly higher corticosterone levels at the early stage of LPS-induced septic shock; whereas TREM2 deficiency neither increased CRH and ACTH nor exacerbated the inflammation in adrenocortical tissue during septic shock. Ex vivo study revealed that Trem2−/− macrophages significantly promoted the expression of steroidogenic enzymes and increased production of corticosterone. Furthermore, Trem2−/− macrophage-derived exosomes were able to mimic Trem2−/− macrophages in enhancing adrenocortical steroidogenesis. ConclusionsAt the early stage of LPS-induced septic shock, corticosterone biosynthesis can be inhibited by macrophage TREM2 in adrenocortical cells, which might partially associate with macrophage-derived exosomes.
Highlights
Sepsis is a life-threatening disease characterized by a dysregulated host response to infection causing organ dysfunction [1]
Triggering receptor expressed on myeloid cells-2 (TREM2) is a novel phagocytic receptor of the immunoglobulin superfamily, mainly expressed by microglia in the central nervous system (CNS) and macrophages in the peripheral organs and tissues [15]
Double immunofluorescence stained with F4/80 and TREM2 antibodies was used to locate the expression of TREM2 in the adrenal gland
Summary
Sepsis is a life-threatening disease characterized by a dysregulated host response to infection causing organ dysfunction [1]. The high mortality rate of sepsis (15~33.5%) is increased up to 40~70% when further progressing to septic shock or suffering from multiple organ failure [3,4,5]. In the development of septic shock, microbes and toxins do activate the immune system and initiate a stress response including a rapid activation of the hypothalamic-pituitary-adrenal (HPA) axis, which leads to production of adrenocorticotrophic hormone (ACTH) and amounts of glucocorticoids (corticosterone in rodents and cortisol in humans) releasing into circulation [6]. Genetic defects or surgical interventions in stress response and adrenal gland contributes to the increased mortality rates when suffered from sepsis [9, 10], indicating that an intact function of glucocorticoids production in adrenal gland is of pivotal importance for sepsis surviving. The role and mode of action of macrophage TREM2 on adrenocortical steroidogenesis remains unclear in septic shock
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