Differential role of the NLRP3 inflammasome in infection and tumorigenesis

Abstract

Dysregulated inflammation is one of the hallmarks of cancer initiation and progression. Emerging evidence indicates that inflammasomes play a central role in regulating immune cell functions in various infections and cancer. Inflammasomes are multimeric complexes consisting of nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs). Among the NLRs, NOD1, NOD2 and NLRP3 respond to a variety of endogenous (i.e. damage-associated molecular patterns) and exogenous (i.e. pathogen-associated molecular patterns) stimuli. The NLRP3 inflammasome is associated with the onset and progression of autoinflammatory and autoimmune diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, and cryopyrin-associated periodic fever syndrome. NLRP3 is also associated with a wide variety of infections and tumorigenesis that are closely correlated with chemotherapy response and prognosis. In this review, we explore the rapidly expanding body of research on the expression and functions of NLRP3 in infections and cancers and outline novel inhibitors targeting the NLRP3 inflammasome that could be developed as therapeutic alternatives to current anticancer treatment.

Keywords: inflammasome; inflammation; tumorigenesis.

Figure 1

Overview of the activation of the NLRP3 inflammasome complex. Two signals are required to activate NLRP3 inflammasome. Various pathogen‐associated molecular patterns (PAMPs) and damage‐associated molecular patterns (DAMPs) induce the nuclear factor‐κB (NF‐κB) ‐signaling cascade and its translocation into the nucleus for transcription of pro‐interleukin‐1β (IL‐1β) and pro–IL‐18, which comprise Signal 1. Pore‐forming toxins and particulates/crystals comprise Signal 2, which induces the oligomerization of NLRP3 and the assembly of the inflammasome complex. Pore‐forming toxins and particulates trigger a potassium (K⁺) efflux to activate the NLRP3 inflammasome complex. Furthermore, mitochondrial degradation and reactive oxygen species (mtROS) initiate the activation of the NLRP3 inflammasome. Finally, active caspase‐1 cleaves gasdermin D to initiate pyroptosis and pro‐IL‐1β and pro‐IL‐18 to initiate the maturation of IL‐1β and IL‐18, respectively.