The implication of targeting PD-1:PD-L1 pathway in treating sepsis through immunostimulatory and anti-inflammatory pathways

Abstract

Sepsis currently remains a major contributor to mortality in the intensive care unit (ICU), with 48.9 million cases reported globally and a mortality rate of 22.5% in 2017, accounting for almost 20% of all-cause mortality worldwide. This highlights the urgent need to improve the understanding and treatment of this condition. Sepsis is now recognized as a dysregulation of the host immune response to infection, characterized by an excessive inflammatory response and immune paralysis. This dysregulation leads to secondary infections, multiple organ dysfunction syndrome (MODS), and ultimately death. PD-L1, a co-inhibitory molecule expressed in immune cells, has emerged as a critical factor in sepsis. Numerous studies have found a significant association between the expression of PD-1/PD-L1 and sepsis, with a particular focus on PD-L1 expressed on neutrophils recently. This review explores the role of PD-1/PD-L1 in immunostimulatory and anti-inflammatory pathways, illustrates the intricate link between PD-1/PD-L1 and sepsis, and summarizes current therapeutic approaches against PD-1/PD-L1 in the treatment and prognosis of sepsis in preclinical and clinical studies.

Keywords: PD-1/PD-L1; immune homeostasis; immunoparalysis; organ damage; sepsis; treatment.

Figure 1

Cellular network diagram of immunoparalysis in sepsis. (I) The expression of PD-1 on T cells and PD-L1 on other immune cells are upregulated during sepsis. (II) Phagocytosis of monocytes/macrophages is compromised, and cytokine production is reduced. (III) The differentiation, proliferation, and activation of DCs are impaired, with inhibitory effect on T cell function. The endotoxin-tolerant DCs express immunosuppressive genes and have direct inhibitory effects on other immune cells. (IV) The apoptosis of B cells increases and the number of Bregs increases. (V) Increased MDSCs inhibit T cells, decrease IL-6 production, and increase the number of Tregs. (VI) Exosomal PD-L1 and PD-L1 increase and induce T cell dysfunction. (VII) The phagocytosis and migration ability of neutrophils were weakened, and TNF-α production was reduced. Neutrophils promote T cell apoptosis, inhibit T cell activation, and increase the amount of Tregs through direct contact, while IFN-γ secreted by T cells in turn increases the number of PD-L1+ neutrophils. PD-1, programmed cell death- 1; PD-L1, programmed cell death-ligand 1; MHC, major history complex; TCR, T cell receptor; CTLA-4, cytotoxic T-lymphocyte associated protein 4; TGF, transforming growth factor; IL-6, interleukin 6; TNF-α, tumor necrosis factor α; IFN-γ, interferon γ; IRAK, interleukin receptor-associated kinase; ITSM, immunoreceptor tyrosine-based switching motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; SHP1/2, Src homology-2 containing protein tyrosine phosphatase 1/2; PI3K, phosphatidylinositol 3 kinase; AKT (PKB), protein kinase B; ERK, extracellular regulated protein kinases; MAPK, mitogenactivated protein kinase; APC, antigen-presenting cell; DCs, dendritic cells; Bcl-2, B lymphoblastoma-2 gene.

Figure 2

Dysfunction of PD-L1+ neutrophils. (I) The mobilization of PD-L1+ neutrophils is impaired. During fungal infection, β-glucans activate Dectin-1 and regulate the production of CXCL1/2, resulting in the accumulation of neutrophils in the bone marrow and further weakening the host immunity. (II) The migration dysfunction of PD-L1+ neutrophils and delayed apoptosis mediated by PKM2/STAT1 lead to excessive accumulation of neutrophils in non-targeted organs, resulting in organ damage. (III) Phagocytosis of PD-L1+ neutrophils is impaired, and the release of TNF-α is reduced. PD-L1, programmed cell death-ligand 1; JAK2, janus kinase 2; STAT3, recombinant signal transducer and activator of transcription 3; PKM2, recombinant pyruvate kinase M2; CXCL1/2, chemokine (C-X-C motif) ligand 1/2; TNF-α, tumor necrosis factor α.