Metabolic regulators of enigmatic inflammasomes in autoimmune diseases and crosstalk with innate immune receptors

Abstract

Nucleotide-binding domain and leucine-rich repeat receptor (NLR)-mediated inflammasome activation is important in host response to microbes, danger-associated molecular patterns (DAMPs) and metabolic disease. Some NLRs have been shown to interact with distinct cell metabolic pathways and cause negative regulation, tumorigenesis and autoimmune disorders, interacting with multiple innate immune receptors to modulate disease. NLR activation is therefore crucial in host response and in the regulation of metabolic pathways that can trigger a wide range of immunometabolic diseases or syndromes. However, the exact mode by which some of the less well-studied NLR inflammasomes are activated, interact with other metabolites and immune receptors, and the role they play in the progression of metabolic diseases is still not fully elucidated. In this study, we review up-to-date evidence regarding NLR function in metabolic pathways and the interplay with other immune receptors involved in GPCR signalling, gut microbiota and the complement system, in order to gain a better understanding of its link to disease processes.

Keywords: GPCR signalling; complement system; gut microbiota; immunometabolic diseases; inflammasome; metabolic reprogramming.

FIGURE 1

Activation of NLRs, non‐canonical and canonical inflammasomes. Structure and activating ligands of canonical NLRP3, NLRC4, NLRP1 (human NLRP1 inflammasome contains PYD, mouse NLRP1 does not), NLRP6 and AIM2 inflammasomes, as well as non‐canonical NLRP3 inflammasome, and NLRC3 and NLRX1, which are non‐inflammasome forming NLRs. Human and mouse NLRs and AIM2 get activated in response to distinct ligands. Double‐stranded RNA (dsRNA) is an activator of human NLRP1 while anthrax lethal toxin activates murine NLRP1B. NLRC4 inflammasome gets activated by T3SS/T4SS indirectly by detecting flagellin, or directly by detecting the T3SS rod protein. Mouse NAIP5 and 6 detect flagellin, mouse NAIP 1 and 2 as well as human NAIP respond to proteins of type III secretion systems (T3SS). Upon ligand binding, NAIP and NLRC4 assemble into an oligomerized inflammasome. Among several bacterial ligands of AIM2, Francisella tularensis and Listeria monocytogenes act as activators of mouse AIM2 inflammasome. DNA and RNA viruses are ligands to mostly human AIM2 inflammasome. Canonical activation of inflammasomes results in oligomerization of ASC into speck complexes, recruiting pro‐caspase 1 leading to self‐cleavage and activation of caspase 1. Caspase 1 cleaves pro‐IL‐1β (produced by NFκB‐induced upregulation) and pro‐IL‐18, as well as GSDMD cleavage. The N‐terminal fragment of GSDMD forms pores on the cell membrane and enables secretion of IL‐1β and IL‐18, with subsequent pyroptosis. Non‐canonical NLRP3 inflammasome activation occurs via human caspase 4 and 5 or murine caspase 11. Sensing of intracellular LPS by pro‐caspase 11 leads to caspase 11 activation and subsequent GSDMD cleavage, as well as K⁺ efflux promoting the activation of NLRP3‐ASC‐caspase 1 pathway

FIGURE 2

Metabolic regulators of the inflammasome in the crossroads with: GPCR signalling, host–microbiota communication and the complement system. (A) GPCRs that activate or inhibit NLRP3 inflammasome by metabolites. GPR43 and/or GPR109A act as SCFA (mainly acetate) receptors to induce NLRP3 inflammasome activation via K⁺ efflux, increased Ca²⁺ mobilization and membrane hyperpolarization in gut epithelial cells, or to repress NLRP3 inflammasome activation via decreased Ca²⁺ mobilization and activation of sAC and PKA in BMDMs. GPR120, receptor of the ω‐3 FA DHA, inhibits NLRP3 activation through suppression of NF‐κB and binding of β‐arrestin 2 (Arrβ2) to NLRP3, impeding its assembly. BHB inhibits NLRP3 activation via an undefined Gαi‐coupled GPCR. TGR5 and EP4, receptors of bile acids (LCA) and PGE₂, respectively, both inhibit NLRP3 via cAMP‐PKA signalling, causing NLRP3 phosphorylation. PGE₂ can also promote NLRP3 priming via EP4‐cAMP‐PKA signalling leading to NF‐κB activation in BMDMs. The bile acid CDCA can bind TRG5 leading to NLRP3 activation through K⁺ efflux and ROS production. (B) Inflammasome activation in the gut by metabolites leads to IL‐18 release which promotes AMP production and secretion by nearby cells, controlling the gut microbial composition. Upon dysbiosis induction, histamine and spermine inhibit NLRP6‐dependent IL‐18 and AMP, supporting the dysbiotic microbiota. Taurine reduces spermine and histamine levels and induces IL‐18 secretion and improved microbiota composition. H₂S inhibits NLRP3 inflammasome and IL‐1β secretion in DSS‐induced colitis colons via reduced ROS and Nrf2 activation.The bile acid analogue BAA473 activates pyrin inflammasome in intestinal epithelial cells leading to IL‐18 secretion. (C) The complement system activates NLRP3 inflammasome via metabolic changes. Activation of C3aR drives ATP efflux from the cytosol and ERK1/2 phosphorylation. ATP efflux triggered by C3a activates P2X7, leading to NLRP3 activation. C5a binding to C5aR1 triggers NLRP3 inflammasome priming and activation via ROS production, lysosomal damage and cathepsin B activity. CD46‐CYT‐1 upregulated by TCR stimulation through autocrine C3b production drives upregulation of LAT1 and GLUT1, which mediate nutrient influx into the cell, as well as LAMTOR5. LAMTOR5 drives mTORC1 activation (a known NLRP3 inflammasome activator) leading to increased glycolysis and Th1 cell induction. CD46‐CYT‐1 signalling also primes NLRP3 inflammasome by upregulating IL‐1β and NLRP3. Membrane attack complex deposition drives NLRP3 activation in human lung epithelial cells via Ca²⁺ influx, increased [Ca²⁺]i in the cytosol and endoplasmic reticulum (ER) stores, subsequent mitochondrial [Ca²⁺]i uptake and alteration of mitochondrial membrane potential