Sepsis-induced immunosuppression: mechanisms, biomarkers and immunotherapy

Abstract

Sepsis, a life-threatening organ dysfunction resulting from a dysregulated host response to infection, initiates a complex immune response that varies over time, characterized by sustained excessive inflammation and immunosuppression. Sepsis-induced immunosuppression is now recognized as a major cause of septic death, and identifying effective strategies to counteract it poses a significant challenge. This immunosuppression results from the disruption of immune homeostasis, characterized by the abnormal death of immune effector cells, hyperproliferation of immune suppressor cells, release of anti-inflammatory cytokines, and expression of immune checkpoints. Preclinical studies targeting immunosuppression, particularly with immune checkpoint inhibitors, have shown promise in reversing immunocyte dysfunctions and establishing host resistance to pathogens. Here, our review highlights the mechanisms of sepsis-induced immunosuppression and current diagnostic biomarkers, as well as immune-enhancing strategies evaluated in septic patients and therapeutics under investigation.

Keywords: biomarkers; immunology; immunosuppression; sepsis; therapy.

Figure 1

Overview of homeostatic disturbance in sepsis. During sepsis, the immune response is initiated when the host recognizes PAMPs and DAMPs involving both innate and adaptive immune system. Several mechanisms, including the proliferation of inflammatory cells, secretion of inflammatory cytokines and activation of the complement system, can escalate pro-inflammatory responses. Conversely, heightened abnormal death of immune effectors cells, production of anti-inflammatory cytokines, expansion of immunosuppressive cells and expression of specific immune checkpoints can exacerbate anti-inflammatory responses. Dominance of the pro-inflammatory response often correlates with a massive cytokine storm, leading to MODs. Conversely, the dominance of the anti-inflammatory response typically results in secondary infections and a poor prognosis. The figure was created via BioRender (https://BioRender.com).

Figure 2

Time course and transition from hyper-inflammation to immunosuppression phase in sepsis. Both pro-inflammatory and anti-inflammatory responses are rapidly triggered after the onset of sepsis, and the transition from immune homeostasis to immune imbalance plays vital roles in the pathogenesis and progression of sepsis. The early stage is mainly dominated by the hyper-inflammation, during which the excessive “cytokine storm” often lead to early death of patients. On the contrary, if the body can restore normal immunity and rebalance, patients will enter the recovery stage or be gradually dominated by immunosuppression and suffer late or long-term death due to secondary infections, immune dysfunction and chronic catabolism. The figure was created via BioRender (https://BioRender.com).

Figure 3

Mechanisms underlying immunosuppression in sepsis. Sepsis-induced immunosuppression involves dysfunction of immune effector cells, expansion of immune suppressive cells, secretion of anti-inflammatory mediators and expression of immune checkpoints, primarily concerning neutrophils, T lymphocytes, B lymphocytes, macrophages and dendritic cells (DCs), et al. The figure was created via BioRender (https://BioRender.com).

Figure 4

The role of anti-inflammatory cytokines in modulating immune responses and contributing to sepsis related immunosuppression. During the occurrence and progression of immunosuppression in sepsis, IL-4, IL-10, IL-27, TGF-β, IL-37, and IL-38 act as key anti-inflammatory mediators, promoting the differentiation of naïve T cells into T helper (Th) subsets, including Th2, and Th17. These mediators also suppress the activation of immune cells such as DCs, monocytes, and promote the polarization of macrophages toward an anti-inflammatory M2 phenotype. Additionally, they enhance the proliferation of Tregs and MDSCs, which further contribute to the suppression of inflammation. Notably, the reduction in HLA expression on immune cells also happened as a result of the activation of these anti-inflammatory signals. The figure was created via BioRender (https://BioRender.com).

Figure 5

Impacts of immunosuppression on the immune cell functionality during sepsis. Immunosuppression during sepsis induces multifaceted dysfunction across immune cell populations. In macrophages, M1 subsets demonstrate impaired phagocytic capacity, while M2 macrophages exhibit upregulated secretion of anti-inflammatory mediators. Immature neutrophils acquire pathological functions, including suppression of T lymphocyte proliferation, exacerbation of neutrophil dysfunction, and potentiation of neutrophil extracellular traps (NETs) formation. T cells show reduced proliferative activity and diminished Th1 cytokine production, whereas B cells display decreased immunoglobulin secretion alongside elevated IL-10 production and MHC II expression. NK cells manifest compromised cytotoxicity coupled with reduced IFN-γ and TNF-α expression, collectively exacerbating T cell insufficiency. Notably, regulatory cell populations, including Tregs and the recently characterized ILCs, undergo expansion with concomitant increases in IL-10 production. The figure was created via BioRender (https://BioRender.com).

Figure 6

Targeting Immunomodulatory Therapy for Sepsis-immunosuppression. The immunomodulatory strategies of sepsis-induced immunosuppression mainly include immune checkpoint inhibitors, interferons and interleukins (IL-7, GM-CSF, IFN-γ, Thymosin alpha 1), MSCs and intravenous immunoglobulin. The figure was created via BioRender (https://BioRender.com).