Immunoadjuvant therapy in the regulation of cell death in sepsis: recent advances and future directions

Abstract

Sepsis is characterized by a concomitant early pro-inflammatory response by immune cells to an infection, and an opposing anti-inflammatory response that results in protracted immunosuppression. The primary pathological event in sepsis is widespread programmed cell death, or cellular self-sacrifice, of innate and adaptive immune cells, leading to profound immunological suppression. This severe immune dysfunction hampers effective primary pathogen clearance, thereby increasing the risk of secondary opportunistic infections, latent viral reactivation, multiple organ dysfunction, and elevated mortality. The types of cell death include apoptosis (type I programmed cell death), autophagy (type II programmed cell death), NETosis (a program for formation of neutrophil extracellular traps (NETs)) and other programmed cell deaths like pyroptosis, ferroptosis, necroptosis, each contributing to immunosuppression in distinct ways during the later phases of sepsis. Extensive apoptosis of lymphocytes, such as CD4+, CD8+ T cells, and B cells, is strongly associated with immunosuppression. Apoptosis of dendritic cells further compromises T and B cell survival and can induce T cell anergy or promote regulatory Treg cell proliferation. Moreover, delayed apoptosis and impaired neutrophil function contribute to nosocomial infections and immune dysfunction in sepsis. Interestingly, aberrant NETosis and the subsequent depletion of mature neutrophils also trigger immunosuppression, and neutrophil pyroptosis can positively regulate NETosis. The interaction between programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1) plays a key role in T cell modulation and neutrophil apoptosis in sepsis. The dendritic cell growth factor, Fms-like tyrosine kinase (FLTEL), increases DC numbers, enhances CD 28 expression, attenuates PD-L1, and improves survival in sepsis. Recently, immunoadjuvant therapies have attracted attention for their potential to restore host physiological immunity and homeostasis in patients with sepsis. This review focuses on several potential immunotherapeutic agents designed to bolster suppressed innate and adaptive immune responses in the management of sepsis.

Keywords: NETosis; apoptosis; autophagy; ferroptosis; immunosuppression; necroptosis cell death; pyroptosis; sepsis.

Figure 1

Overview of sepsis-attributed immunosuppression: Impairment of innate immune cell death pathways. In sepsis, alteration of cytokines (upregulated IL-1, IL-10) and reduced antigen presentation (downregulated HLA-DR) is marked. Sepsis slows neutrophil apoptosis and augments NETosis, autophagy, and pyroptosis, like cell deaths, resulting in an increase in the number of immature neutrophils, T cell proliferation inhibitory MDSCs, and the depletion of mature neutrophils. Monocytes and macrophages also encounter increased apoptosis, pyroptosis, autophagy, and NETosis-like cell death. Dendritic cells undergo extensive apoptosis, which induces a tolerogenic state. Unlike increased NETosis, DCs have less potential to undergo autophagy in sepsis. The PD-1/PD L-1 axis plays a significant role in the induction of all these cell death pathways. All these different cell death patterns contribute to immunosuppression in sepsis.

Figure 2

Sepsis-induced immunosuppression: impairment of adaptive immune cell death pathways. Upregulated IL-10 and downregulated CD8 and HLA-DR is notable in sepsis. B-cells undergo apoptosis in sepsis, resulting in a reduction of overall B-cell populations and impairment of the antigen-presenting role of B-cells. Sepsis causes excessive T-cell apoptosis, causing lymphopenia and ultimate immunosuppression. On the contrary, reduced T-cell autophagy in sepsis also contributes to immunosuppression. PD-1 and PD-L-1 play a vital role in this immunosuppression.