The Roles of Inflammasomes in Host Defense against Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (MTB) infection is characterized by granulomatous lung lesions and systemic inflammatory responses during active disease. Inflammasome activation is involved in regulation of inflammation. Inflammasomes are multiprotein complexes serving a platform for activation of caspase-1, which cleaves the proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 into their active forms. These cytokines play an essential role in MTB control. MTB infection triggers activation of the nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes in vitro, but only AIM2 and apoptosis-associated speck-like protein containing a caspase-activation recruitment domain (ASC), rather than NLRP3 or caspase-1, favor host survival and restriction of mycobacterial replication in vivo. Interferons (IFNs) inhibits MTB-induced inflammasome activation and IL-1 signaling. In this review, we focus on activation and regulation of the NLRP3 and AIM2 inflammasomes after exposure to MTB, as well as the effect of inflammasome activation on host defense against the infection.

Keywords: AIM2; IFN; Mycobacterium tuberculosis; NLRP3; inflammasome.

Figure 1

TLRs are involved in regulation of Mycobacterium tuberculosis (MTB)-induced production of proinflammatory cytokines. Stimulation with MTB [90], lipoarabinomannan [91] or 19 kDa lipoprotein from MTB [92] causes formation of TLR1/TLR2 heterodimer [93,94], inducing clustering of lipid rafts through interaction with protein kinase C ζ (PKCζ) and subsequent ROS formation [92]. Accumulation of ROS activates mitogen-activated protein kinases (MAPKs) [95,96], which promotes expression and secretion of proinflammatory cytokines via activation of NF-κB signaling pathway [97,98,99]. The class A scavenger receptor macrophage receptor with collagenous structure (MARCO) tethers trehalose 6,6’-dimycolate (TDM/cord factor) that is the predominant cell wall glycolipid of MTB to the macrophages to activate TLR2 [100]. Toll-interacting protein (TOLLIP) negatively regulates TLR2- and TLR4-mediated production of proinflammatory cytokines [101]. MTB stimulation activates TLR4 [81,102], which facilitates NF-κB-dependent production of proinflammatory cytokines [103]. TLR4 expression is negatively controlled by some microRNAs, including MiR-21-5p [104], MiR-708-5p [105] and MiR-1178 [106]. TLR9 cooperates with TLR2 to promote generation of proinflammatory cytokines [82].

Figure 2

The role of MyD88 in NLRP3 inflammasome activation. Activated TLRs, including TLR2 [111,112], TLR4 [113,114], TLR5 [115], TLR2/6 heterodimer [116], TLR1/2 heterodimer [117] and TLR4/5 [118,119], facilitate activation of NF-κB signaling in a MyD88-dependent manner, which promotes NLRP3 inflammasome activation in the priming step [120]. ADP ribosylation factor 6 (ARF6) regulates synthesis of phosphatidylinositol 4,5-bisphosphate (PIP2) [121], which binds preferentially to Toll-interleukin 1 receptor (TIR) domain containing adaptor protein (TIRAP), provoking TIRAP transport to plasma membrane and subsequent MyD88 recruitment to activated TLR4 [122], TLR2 [123] and TLR5 [124]. TIRAP is dispensable for NF-κB activation following stimulation with high concentrations of TLR2 ligands [125]. MyD88 dimers recruit IL-1R–associated kinase 4 (IRAK4) and IRAK1 through its intermediate domain and N-terminal death domain, respectively [126,127]. This bridges the IRAK1 and IRAK4 kinase domains in close association, causing phosphorylation of IRAK1 by IRAK4 and subsequent IRAK1 autophosphorylation [128,129]. IRAK1 dissociates from MyD88 and TOLLIP after phosphorylation [130], and interacts with tumor necrosis factor receptor associated factor 6 (TRAF6) [128], leading to activation of NF-κB in TAK1-dependent and MEKK3-dependent pathways [131]. Abbreviation: MEKK3, MAPK/ERK kinase kinase 3; TAK1, transforming growth factor (TGF)-β-activated kinase 1; TAB1, TGF-β activated kinase 1 binding protein 1; Ubc13, ubiquitin-conjugating enzyme 13; Uev1A, Ubiquitin-conjugating enzyme variant 1A.