Advances in the Study of Immunosuppressive Mechanisms in Sepsis

Abstract

Sepsis is a life-threatening disease caused by a systemic infection that triggers a dysregulated immune response. Sepsis is an important cause of death in intensive care units (ICUs), poses a major threat to human health, and is a common cause of death in ICUs worldwide. The pathogenesis of sepsis is intricate and involves a complex interplay of pro- and anti-inflammatory mechanisms that can lead to excessive inflammation, immunosuppression, and potentially long-term immune disorders. Recent evidence highlights the importance of immunosuppression in sepsis. Immunosuppression is recognized as a predisposing factor for increased susceptibility to secondary infections and mortality in patients. Immunosuppression due to sepsis increases a patient's chance of re-infection and increases organ load. In addition, antibiotics, fluid resuscitation, and organ support therapy have limited impact on the prognosis of septic patients. Therapeutic approaches by suppressing excessive inflammation have not achieved the desired results in clinical trials. Research into immunosuppression has brought new hope for the treatment of sepsis, and a number of therapeutic approaches have demonstrated the potential of immunostimulatory therapies. In this article, we will focus on the mechanisms of immunosuppression and markers of immune monitoring in sepsis and describe various targets for immunostimulatory therapy in sepsis.

Keywords: hyperinflammation; immune cell; immunosuppression; sepsis.

Figure 1

The pathogenesis of sepsis is characterized by both proinflammatory and anti-inflammatory mechanisms, and it is now believed that proinflammatory and anti-inflammatory can coexist, and that normally, proinflammatory and anti-inflammatory are in a dynamic equilibrium, which is disrupted by sepsis, which early on leads to the massive secretion of proinflammatory factors, reprogramming of the immune cells, and activation of the complement and coagulation systems, which further leads to a cytokine storm. Anti-inflammatory cytokines may be released subsequently or concurrently, and as the disease progresses, over-activation of the immune system leads to depletion of immune cells and sepsis progresses to an immunosuppressed state. The mechanisms of immunosuppression in sepsis and its complexity involve immune cell regulation, apoptosis autophagy, endotoxin tolerance, central nervous system, and metabolic changes. Therapies targeting immunosuppression in sepsis have the potential to be realized through these mechanisms.

Figure 2

Anti-inflammatory cytokines are a very critical part of the immunosuppressive mechanism in sepsis. The mechanism of action of anti-inflammatory cytokines is very complex. The main anti-inflammatory cytokines are IL-4, IL-10, IL-33, IL-35, IL-37, and IL-38. IL-4 promotes the differentiation of CD4⁺ T lymphocytes into TH2 cells and releases anti-inflammatory cytokines. IL-10 can inhibit pro-inflammatory cytokine secretion and promote immunosuppressive cells Tregs with MDSCs. IL-33 promotes the immunosuppressive effects of IL-10 and promotes macrophage like M2 transformation. IL-35 promotes Tregs. IL-37 inhibits T lymphocyte and monocyte immune function. IL-38 inhibits TH17 and promotes Tregs.