IRF3 function and immunological gaps in sepsis

Abstract

Lipopolysaccharide (LPS) induces potent cell activation via Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD-2), often leading to septic death and cytokine storm. TLR4 signaling is diverted to the classical acute innate immune, inflammation-driving pathway in conjunction with the classical NF-κB pivot of MyD88, leading to epigenetic linkage shifts in nuclear pro-inflammatory transcription and chromatin structure-function; in addition, TLR4 signaling to the TIR domain-containing adapter-induced IFN-β (TRIF) apparatus and to nuclear pivots that signal the association of interferons alpha and beta (IFN-α and IFN-β) with acute inflammation, often coupled with oxidants favor inhibition or resistance to tissue injury. Although the immune response to LPS, which causes sepsis, has been clarified in this manner, there are still many current gaps in sepsis immunology to reduce mortality. Recently, selective agonists and inhibitors of LPS signals have been reported, and there are scattered reports on LPS tolerance and control of sepsis development. In particular, IRF3 signaling has been reported to be involved not only in sepsis but also in increased pathogen clearance associated with changes in the gut microbiota. Here, we summarize the LPS recognition system, main findings related to the IRF3, and finally immunological gaps in sepsis.

Keywords: IRF3 signaling; MyD88-depending pathway; TLR4 signaling; lipopolysaccharide (LPS); sepsis control.

Figure 1

Extra- and Intra-cellular LPS recognition mechanism. TLR4 mediated NLRP3 (canonical) inflammasome signaling cascade consists of NLRP3, ASC and caspase-1 which leads to maturation and release of IL-1β and IL-18. Two distinct pathways are involved to trigger this signaling cascade. The first one is priming initiated with the recognition of extracellular LPS by TLR4. This activates NF-κB leading to pro IL-1β and pro IL-18 and up-regulates the expression of NLRP3 and pro-caspase-1. Expression of caspase-11 is also elevated by IFN-β/IFNR signaling. IRF3 and STING function as primary stimulator for IFN-β production. Another one is activation induced in response to intracellular LPS which is recognized by caspase-11 (Human: caspase-4/5). This results in the formation of non-canonical inflammasome complex and then activation, that is followed by pyroptosis through GSDMD cleavage. Meanwhile, the activation of IL-1β and IL-18 during the process of pyroptosis is mediated by processing of precursors of these cytokines by caspase-1.