1. Introduction

Despite the development of chemotherapy and vaccine programs, tuberculosis (TB) continues to lead to increasing death tolls and poses a serious threat to global public health ^[1]. It is one of the top 10 causes of mortality and the leading cause from a single infectious pathogen. WHO estimated that 1.5 million people died from TB in 2018 (https://www.who.int/news-room/fact-sheets/detail/tuberculosis). Approximately one-third of the world’s population is infected with MTB, the main causative agent of TB, and 5-10% of the population develops active TB [2]^[2]. .MTB can infect the host for decades without causing clinical manifestations, only to reactivate in compromised immunity. Bacterial replication results in a robust granulomatous inflammatory response in immunocompromised patients. Inflammation is indispensable for initial control of infection, and also helps disseminate MTB to susceptible individuals in the community [3]

^[3] IL-1β and IL-18, members of IL-1 family, are potent proinflammatory cytokines [4-6]^[4][5][6]. They play a critical role in host defence against MTB infection. Mice deficient in IL-1β or IL-1 receptor type I (IL-1R1) have been shown to be highly susceptible to infection with MTB, as reflected by decreased survival time, increased bacterial burden in lungs and bronchoalveolar lavage fluid (BALF) and extensive pulmonary necrosis [7,8]^[7][8]. IL-18 deficiency in mice elicits higher bacterial burden in lung tissues and larger granulomas in the lungs and spleens. Administering exogenous recombinant IL-18 subcutaneously to IL-18-disrupted mice reduces the sizes of the granulomatous lesions and bacterial load.^[9]. IL-1β activity is rigorously controlled both at the transcriptional and post-translational levels. IL-1β and IL-18 are synthesized as biologically inactive intracellular precursors which are mainly dependent on nuclear factor-κB (NF-κB) pathway. Then the precursors are cleaved into the bioactive forms by active caspase-1 [10,11]^[10][11] or other enzymes such as proteinase-3 (PR3) [12^[12][13],13], neutrophil elastase [14,15]^[14][15], cathepsin G ^[16] and matrix metalloproteinases (MMPs) [17,18]^[17][18]. Caspase-1 activation is caused by assembly of inflammasome, which is a multiprotein platform for processing and secretion of proinflammatory cytokines as well as initiation of pyroptosis ^[19]. Inflammasomes play a critical role in host defence against pathogens. However, aberrant activation is detrimental, causing tissue damage and even higher mortality. In this review, we discuss the interaction of MTB with inflammasomes and the roles in host defence against the bacteria.

2. A Brief Introduction to Inflammasomes

Inflammasomes, major components of the innate immune system, consist of sensor proteins, ASC that is not necessary for all inflammasomes such as the NLRP1 and NLRC4 inflammasomes, and executor caspase-1. The sensors interacts with ASC and caspase-1 following detecting pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), leading to assembly of inflammasomes and activation of caspase-1 ^[20]. Active caspase-1 mediates maturation and release of proinflammatory cytokines such as IL-1β and IL-18 as well as pyroptosis, a programmed necrotic cell death which is mediated via gasdermin D’s membrane pore-forming activity [21,22]^[21][22]. Among inflammasomes, the NLRP3 and AIM2 inflammasomes are extensively described. Upon exposure to chemically- and structurally-unrelated agonists, NLRP3 is activated via its association with mitochondrion-derived molecules, such as cardiolipin ^[23] and mitochondrial DNA (mtDNA) ^[24]. AIM2 senses non-sequence-specific DNA via electrostatic attraction between the double-stranded DNA (dsDNA) sugar-phosphate backbone and the positively charged HIN (hematopoietic expression, interferon-inducible nature, and nuclear localization) domain residues [25^[25][26],26], oligomerizes at multiple binding sites in dsDNA ^[27], and recruits ASC and caspase-1 to assemble the AIM2 inflammasome ^[28].

3. MTB and the NLRP3 inflammasome

Many reports have documented that infection with MTB triggers NLRP3 inflammasome activation in vitro. MTB infection activates the NLRP3 inflammasome in several cell types, including THP-1 monocyte-derived macrophages ^[29], primary human macrophages derived from peripheral blood mononuclear cells ^[30], murine bone marrow-derived macrophages (BMDMs) ^[31], bone marrow-derived dendritic cells (BMDCs) ^[32], murine retinal pigment epitheliums ^[33], and primary murine microglial cells ^[34], from 6 hours postinfection (hpi) ^[32] to 24 hpi [31^[31][35],35], based on the fact that maturation of caspase-1 and release of IL-1β are suppressed in cells isolated from Nlrp3^-/-, Asc^-/- or caspase-1^-/- mice ^[32], or after inhibition with lentivirus-mediated shRNA [29^[29][36],36], siRNA ^[30] or inhibitors (Ac-YVAD-fmk ^[29] or VX765 ^[37] for caspase-1, MCC950 for NLRP3 ^[37]). MTB H37Rv is more efficient in invading type II alveolar epithelial cells than H37Ra ^[38]. MTB Infection leads to release of proinflammatory cytokines, including IL-8, IL-6 and TNF-α in A549 alveolar epithelial cells ^[39]. It is debatable that MTB activates the NLRP3 inflammasome in RAW264.7 ^[40], because ASC, a necessary component for the NLRP3 inflammasome, is absent in this cell line [41,42]^[41][42]. NLRP3 inflammasome activation restricts mycobacterial growth in macrophages. Caspase-1 overexpression represses mycobacterial growth in THP-1 macrophages ^[29]. Human monocyte–derived macrophages from patients harboring genetic variants in NLRP3 and CARD8 secret higher levels of IL-1β ^[43], and display increased MTB growth control ^[44]. Besides MTB, other mycobacterium pathogens, including Mycobacterium kansasii ^[45], Mycobacterium abscessus ^[46] and M. marinum ^[47], are also able to trigger NLRP3 inflammasome activation, while attenuated vaccine strain Mycobacterium bovis bacillus Calmette-Guérin (BCG) fails to activate NLRP3 ^[32].

MTB activates the NLRP3 inflammasome via several constituents, including ESX-1 secretion system ^[35], Rv1579c (also called EST12) ^[48], Rv0878c (also called PPE13) ^[49], the cell wall component mannosylated lipoarabinomannan ^[29] and dsRNA ^[33]. MTB damages phagosomal and plasma membranes during phagocytosis of bacteria, leading to K+ efflux and activation of NLRP3-dependent IL-1β release and pyroptosis ^[35]. Early secreted antigenic target-6 (ESAT-6) is a marker for mycobacterial viability and an ESX-1 substrate. It disrupts the host cell membranes by causing formation of pores ~4.5 nm in diameter ^[50]. MTB lacking ESAT-6 is unable to induce NLRP3 inflammasome activation, and treatment with purified MTB ESAT-6 triggers caspase-1 activation and IL-1β release. Additionally, ESAT-6 facilitates the delivery of immunostimulatory bacterial products such as AG85 into the cytosol, further augmenting NLRP3 inflammasome activation [29,33]^[29][33]. MTB induces IL-18 expression at both mRNA and protein levels via ESAT-6 in alveolar epithelial cells. Stimulation with ESAT-6 triggers ERK and p38 MAPK phosphorylation and production of ROS, which promotes IL-8 transcription and mRNA stability ^[51]. Stimulation with M. bovis BCG complemented with region of difference 1 (RD1), which encodes a part of the ESX-1 secretion system, induces IL-1β release ^[32]. Rv1579c, secreted from MTB H37Rv RD3, interacts with the receptor for activated C kinase 1 (RACK1) via its amino acid Y80 at the C-terminus, then recruits ubiquitin C-terminal hydrolase L5 (UCHL5) to deubiquitinate NLRP3, and finally activate the NLRP3 inflammasome ^[48].

In spite of the role of the NLRP3 inflammasome in host defence against MTB which is demonstrated by plenty of in vitro studies, in vivo studies show that only ASC mediates host protection during chronic MTB infection, while NLRP3 and caspase-1 are dispensable ^[36]. MTB bacterial burden in lungs and spleens, IL-1β and IL-1α concentrations in lung homogenates, the size, morphology and cellular composition of the lung lesions are not affected by NLRP3 absence following infection with virulent MTB via aerosol ^[32]. Nlrp3^-/- mice also have a similar survival profile to WT controls. Compared to WT mice, Caspase-1^-/- mice display similar levels of bacteria in the lungs and survival profile as well as even higher levels of IL-1β in lung homogenate extracts. ASC disruption leads to decreased survival time and fewer granulomas, although it has no effect on mycobacterial burden in the lungs ^[36]. Thus, Nlpr3^-/- and caspase-1^-/- mice have compensatory mechanisms of processing IL-1β and forming organized granulomas, and ASC is involved in host defence against MTB in NLRP3- and caspase-1-independent manners.

4. MTB and the AIM2 Inflammasome

That MTB infection activates or inhibits the AIM2 inflammasome is of debate. On the one hand, MTB residing in the phagosomes permeabilizes the phagosomal membrane early after infection via the ESX-1 secretion system, which results in release of phagosomal contents, including MTB and its DNA, into the cytosol ^[52]. How DNA is liberated from MTB is still unclear. Saiga and colleagues found that released DNA is sensed by and co-localized with AIM2, provoking AIM2 inflammasome activation. Compared to peritoneal macrophages from WT mice, cleavage of caspase-1 and expression of IL-1β and IL-18 at both the mRNA and protein levels are reduced in the cells from Aim2^-/- mice following infection with MTB ^[53]. M. bovis, a member of the MTB complex, is also able to cause TB in human beings. Its genome sequence is more than 99.95% identical to that of MTB ^[54]. Yang and colleagues found that M. bovis challenge induces upregulation of AIM2 at or after 24 hpi in J774A.1 macrophages and BMDMs. The siRNA-mediated knockdown of AIM2 expression impairs caspase-1 activation and IL-1β secretion, as well as release of lactate dehydrogenase (LDH) at 24 hpi in J774A.1 cells ^[55]. On the other hand, Shah and colleagues found that IL-1β release is inversely correlated with the virulence in mycobacterial species based on the detection of IL-1β levels in the culture supernatant following infection with Mycobacterium smegmatis, Mycobacterium fortuitum, M. kansasii, MTB H37Ra and MTB H37Rv. Aim2 deletion makes no change to IL-1β secretion in LPS-primed BMDCs at 16 hpi after challenging with MTB H37Rv. LPS-primed cells pretreated with MTB H37Rv, but not ESAT-6 deletion mutant, secrets less IL-1β and IL-18 in response to M. smegmatis or poly(dA:dT), indicating that virulent MTB strains inhibits AIM2-dependent IL-1β release ^[56]. These two different conclusions may result from the two following reasons: firstly, Shah and colleagues used LPS-primed BMDCs, while Saiga et al and Yang et al utilized the cells that have not been pretreated with LPS. MTB infection activates the NLRP3 inflammasome, and LPS is supposed to promote NLRP3-dependent IL-1β secretion for its function in priming, which is required for NLRP3 activation ^[57]. This may decrease the contribution of AIM2 to MTB-mediated IL-1β release. Besides, priming step is dispensable for AIM2 inflammasome activation, and poly(dA:dT) is able to activate caspase-1 in an AIM2-dependent manner in the absence of LPS ^[57]. Whether MTB pretreatment induces reduced IL-1β release in response to only poly(dA:dT) is still unclear. M. smegmatis without LPS induces little IL-1β release in J774A.1 cells and BMDMs ^[58]. Thus, more evidence is needed to support that the MTB infection inhibits AIM2 inflammasome activation and resultant IL-1β release. Secondly, Saiga and colleagues used BMDCs, while BMDMs and J774A.1 macrophages were used in the former two studies. Besides AIM2, MTB DNA released into the cytosol can also be sensed by cyclic GMP-AMP synthase (cGAS) [59,60]^[59][60] and interferon-γ inducible protein 204 (IFI204) [59,61]^[59][61]. This triggers activation of type I IFNs signaling and autophagy.

AIM2 is indispensable for host defence against MTB infection. Aim2^-/- mice succumb within 7 weeks following intratracheal infection with MTB H37Rv, while WT mice is able to survive at least 8 weeks. At 4 weeks postinfection, higher bacterial load in the lungs and livers, more evident granulomatous changes and increased inflammatory cell infiltration in the lungs were found in Aim2^-/- mice. At 3 weeks after infection, the levels of IL-1β in BALF and IL-18 in serum from Aim2^-/- mice are lower than that from WT mice ^[53].

5. Regulation of Inflammasome Activation during MTB Infection

IFNs inhibit MTB-mediated inflammasome activation. Type I IFNs inhibits production of IL-1α and IL-1β in macrophages and DCs in lungs of MTB-infected mice ^[8], and are detrimental for the control of MTB [62,63]^[62][63]. They play an inhibitory role in IL-1β production at its mRNA level. Addition of exogenous IFN-β or supplementation of culture medium with neutralizing antibody for IFN-α/βreceptor 2 (IFNABR2) affects the expression of IL-1β mRNA, rather than caspase-1 cleavage. M. bovis BCG does not trigger significant mRNA expression of type I IFNs ^[64]. Guarda and colleagues proposed that Type I IFNs inhibit inflammasome activation and IL-1β production through two independent mechanisms. On the one hand, Type I IFNs bind IFNAR, inducing secretion of anti-inflammatory cytokine IL-10. IL-10 interacts with its receptor IL-10R, decreasing the expression of pro-IL-1 at the protein level via activation of signal transducers and activators of transcription 3 (STAT3). The inhibitory effect of IFN-α or IFN-β on expression of pro-IL-1α and pro-IL-1β becomes less prominent in BMDMs isolated from Stat3^-/- or Il-10^-/- mice. Compared to control Stat3^flox/- BMDMs, the NLRP3 agonist aluminum slats-mediated caspase-1 cleavage is not altered in the presence of type I IFNs in Stat3^-/- cells. On the other hand, STAT1 is phosphorylated at tyrosine 701, which mediates inhibition of NLRP3-dependent caspase-1 activation. IFN-α or IFN-β fails to induce inhibition of activated caspase-1 in Stat1^-/- BMDMs in response to aluminum salts. IFN-β inhibits activation of the NLRP1b and NLRP3 inflammasomes, but not the AIM2 and IPAF inflammasomes. IFN-β inhibits caspase-1 activation following stimulation with NLRP3 inducers, including monosodium urate crystals, asbestos, nigericin, ATP and Candida albicans, and the NLRP1b inducer Bacillus anthracis lethal toxin, rather than the AIM2 agonist poly(dA:dT) or the IPAF agonist Salmonella typhimurium, though amounts of mature form and precursor of IL-1β are diminished in all cases ^[65]. IL-1 and type I IFNs mutually regulate each other via prostaglandin E2 (PGE2) to control the balance. Ifnar1 knockout results in increased PGE2 and IL-1β in BALF, and addition of exogenous IFN-β to MTB-infected BMDMs or human MDMs reduces PGE2. Knockout of Il1r1 or IL-1α/β enhances IFN-α and IFN-β at both the mRNA and protein levels ^[66]. CD4+ T cell-derived IFN-γ plays a protective role in MTB control ^[67]. It inhibits expression of IL-1α and IL-1β only in inflammatory monocytes ^[8], and does not influence pro-IL-1 expression as well as caspase-1 activation and IL-1β maturation in BMDMs ^[65]. Meanwhile, IFN-γ facilitates iron export through control of the expression of iron regulatory proteins hepcidin and ferroportin, and prevents MTB-induced intracellular iron sequestration, retarding the bacterial growth by decreasing iron availability ^[68].

3. Concluding Remarks

Remarkable advances in MTB-host interaction have been made. Many studies identified the roles of certain cytokines in host defence against MTB infection. IL-1 plays a protective role, while type I IFNs have a detrimental effect. Most reports demonstrated that MTB triggers NLRP3 inflammasome activation and subsequent maturation and release of proinflammatory cytokines via ESX-1 secretion system and its substrate ESAT-6 in vitro, but NLRP3 and caspase-1 are dispensable for control of MTB in vivo. AIM2 facilitates to restrict MTB replication both in vitro and in vivo. Type I IFNs suppress IL-1β activity through interaction with IFNAR. However, the mechanisms by which IL-1β is regulated is still unclear. AIM2 is indispensable for activities of IL-1β and IL-18, but caspase-1 does not contribute to higher levels of IL-1β in vivo, implicating that AIM2 exerts its protective function in a caspase-1-independent manner after sensing MTB DNA released into the cytosol. Exploration of the role of inflammasome in host defence against MTB infection, especially the regulation of IL-1, contributes to a better understanding of MTB-host interaction and provides potential therapeutic targets for treating TB.

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