The involvement of endoplasmic reticulum stress response in immune dysfunction of dendritic cells after severe thermal injury in mice

Abstract

Suppressed adaptive immune function is one of the major concerns responsible for the development of opportunistic infections and subsequent sepsis with high mortality in severe burns. Endoplasmic reticulum stress (ERS) is the endogenous self-protective mechanism, and it plays an important role in almost every process of living by regulating the balance between homeostasis and apoptosis. The current study investigated the involvement of ERS in the pathogenesis of dysfunction of dendritic cells (DCs) in burn mice. Our results show a significant ERS response in splenic DC after burn injury. Treatment with salubrinal (Sal, reported to protect cells against ERS-induced apoptosis.) decrease the apoptotic rate of DC induced by burns, and promote maturation and activation of DC, as well as the ability to promote T cell proliferation and polarization towards Th1 immunity (all P<0.05). Gene silence of XBP-1 (key molecular in ERS response) results in the increased apoptosis and suppressed phenotypical maturation of splenic DC in burn mice. These results show that the excessive ERS is essential for immunosuppression during severe thermal injury. XBP-1 plays a pivotal role in DC functional immunomodulation in burn mice. Inhibition of apoptotic ERS response benefits mice from major burns.

Sestrin2 protects dendritic cells against endoplasmic reticulum stress-related apoptosis induced by high mobility group box-1 protein

“…HMGB1, one of the key damage-associated molecular patterns, is an important late-acting inflammatory cytokine of sepsis that can be actively secreted by immune cells or passively released by injured or necrotic cells. It has been documented that HMGB1 is critically involved in host immune dysfunction and various diseases [30][31][32] , and it acts as a potent mediator of DC activation, maturation as well as survival [13][14][15][33][34][35] . In the present study, we investigated the proapoptotic effect of HMGB1 stimulation on DC2.4 cells in vitro, showing a time-dependent and dose-dependent manner.…”

“…Our previous studies proved that the overwhelming ERS response in splenic DCs in severe thermal injuries could be the main cause to initiate excessive apoptosis and dysfunction of DCs, thereby resulting in immunosuppression and even death [13][14][15] . The pathophysiological mechanism is highly related to an important late-acting cytokine high mobility group box-1 protein (HMGB1), which is increased markedly in sepsis and plays an important role in provoking inflammation and immune responses.…”

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…These changes indicate that the stimulation of IRE1-XBP1 signaling switched the immunosuppressive phenotype of DCs and thus enhanced tumor progression. The ER stress-induced suppression of DCs has also been observed after a severe thermal injury in mice [147]. Zhu et al [147] reported that a burn injury promoted the appearance of ER stress in splenic DCs which reduced the maturation of these cells and increased their apoptosis.…”

“…The ER stress-induced suppression of DCs has also been observed after a severe thermal injury in mice [147]. Zhu et al [147] reported that a burn injury promoted the appearance of ER stress in splenic DCs which reduced the maturation of these cells and increased their apoptosis. The splenic DCs from injured mice also displayed a reduced capacity to enhance T cell proliferation and Th1 polarization.…”

Influence of Haes-Lx-5% Infusion Solution on the Dna Content of Endocrine Glands Cells Against the Background of Thermal Burn of Skin in Rats

“…Histological, immunological and biochemical manifestations of adenohypophysis [2], adrenal glands [10,18] and thymus [13,28] damages have been established at different times in the course of burn disease, which lead to severe organ damage [23,22]. However, the molecular mechanisms of these disorders remain poorly understood, which makes it difficult to develop pathogenetic treatments for burn disease.…”