Autophagy: A Potential Therapeutic Target for Reversing Sepsis-Induced Immunosuppression

Abstract

Sepsis remains the leading cause of mortality in intensive care units and an intractable condition due to uncontrolled inflammation together with immune suppression. Dysfunction of immune cells is considered as a major cause for poor outcome of septic patients but with little specific treatments. Currently, autophagy that is recognized as an important self-protective mechanism for cellular survival exhibits great potential for maintaining immune homeostasis and alleviating multiple organ failure, which further improves survival of septic animals. The protective effect of autophagy on immune cells covers both innate and adaptive immune responses and refers to various cellular receptors and intracellular signaling. Multiple drugs and measures are reportedly beneficial for septic challenge by inducing autophagy process. Therefore, autophagy might be an effective target for reversing immunosuppression compromised by sepsis.

Keywords: apoptosis; autophagy; immunosuppression; sepsis; treatment.

Figure 1

The effects of autophagy induction on sepsis-induced immune dysfunction. (A) Effects of autophagy in various stages of sepsis. (B) The role of autophagy induction in the function of multiple immune cells. NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, Nod-like receptor family pyrin domain-containing 3; Tregs, regulatory T cells; NETs, neutrophil extracellular traps; DCs, dendritic cells.

Figure 2

The intracellular signals of autophagy induction in immune cells. (A) Autophagy can be induced by bacteria, bacterial toxins such as LPS, and pro-inflammatory cytokines through TLR2 and TLR4. The activation of TLR4 and TLR2 initiate JNK, p38 MAPK, and ERK signaling in Myd88 and TRIF dependent ways, which further induce autophagy by inhibiting mTORC1 complex. NOD1 and NOD2 receptors, vital intracellular pattern recognition receptors, promote the formation of autophagosomes by enhancing the combination between ATG16L1 and invaded bacteria. HMGB1 induces autophagy through releasing Beclin-1 from Bcl2 after binding with Beclin-1. (B) Four major steps are required for autophagic process, including nucleation, elongation, closure, and fusion with lysosome for degradation, which are tightly regulated by autophagy associated proteins. (C) The function of autophagy associated proteins on immune system involves both canonical and non-canonical dependent ways. ATG16L1, autophagy-related 16-like 1 gene; Bcl2, B-cell lymphoma 2; ERK, extracellular signal-regulated kinase; HMGB1, high-mobility group box-1 protein; IL, interleukin; IRAK, interleukin-1 receptor-associated kinase; JNK, c-Jun N-terminal kinase; LAMP, lysosomal-associated membrane protein; LPS, lipopolysaccharide; MHC, major histocompatibility complex; mLST8, mammalian lethal with SEC13 protein; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; Myd88, myeloid differentiation factor 88; NOD, nucleotide-binding oligomerization domain-containing protein; PELI3, pellino E3 ubiquitin protein ligase family member 3; p38 MAPK, p38 mitogen-activated protein kinase; RIP, receptor interacting protein; ROS, reactive oxygen species; TNF, tumor necrosis factor; TRAF, TNF receptor-associated factor; TRIF, TIR-domain-containing adapter-inducing interferon-β.