Activation of the NLRP3 inflammasome by Mycobacterium tuberculosis is uncoupled from susceptibility to active tuberculosis

Abstract

As a hallmark of tuberculosis (TB), Mycobacterium tuberculosis (MTB) induces granulomatous lung lesions and systemic inflammatory responses during active disease. Molecular regulation of inflammation is associated with inflammasome assembly. We determined the extent to which MTB triggers inflammasome activation and how this impacts on the severity of TB in a mouse model. MTB stimulated release of mature IL-1b in macrophages while attenuated M. bovis BCG failed to do so. Tubercle bacilli specifically activated the NLRP3 inflammasome and this propensity was strictly controlled by the virulenceassociated RD1 locus of MTB. However, Nlrp3-deficient mice controlled pulmonary TB, a feature correlated with NLRP3-independent production of IL-1b in infected lungs. Our studies demonstrate that MTB activates the NLRP3 inflammasome in macrophages in an ESX-1-dependent manner. However, during TB, MTB promotes NLRP3-and caspase-1-independent IL-1b release in myeloid cells recruited to lung parenchyma and thus overcomes NLRP3 deficiency in vivo in experimental models.

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

“…44,45 There are a few studies that suggest that the NLRP3 inflammasome has a role in the CNS. These studies have employed the use of NLRP3 knockout mouse lines to suggest that the NLRP3 inflammasome is activated in microglia after Mycobacterium tuberculosis infection 46 as well as by b-amyloid; the latter linking the NLRP3 inflammasome with Alzheimer's disease, 12 but whether the NLRP3 inflammasome components form proteinprotein associations with each other in the CNS needs to be determined ( Figure 1C). THE AIM2 INFLAMMASOME AIM2 is a member of the hemopoietic interferon-inducible nuclear 200 (HIN200) family of proteins and was recently discovered to form an inflammasome.…”

Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

“…+ T cell deficiency results in decreased IFN-g activation of macrophages and intracellular killing of M. tuberculosis (52,53), leading to an accumulation of M. tuberculosis intracellularly and eventually activation of inflammasomes (54). In the present study, we provide evidence that failure to control M. tuberculosis replication in monocytes/macrophages because T cell responses are impaired by HIV-induced CD4 + T cell depletion leads to "default" immune control mechanisms that include inflammasome activation in monocytes, and that this is greatest in those HIV/TB patients who subsequently develop TB-IRIS after cART is commenced.…”

Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

“…The function of the ESX-1 system was linked to escape of Mtb out of the phagosome at later stages of the infection, which coincided with host cell necrosis induction (Simeone et al 2012). The Mtb EsxA protein is important in forming pores in the phagosomal membrane (Wong and Jacobs 2011), which is essential for subsequent NLRP3-inflammasome activation, because esxA Mtb mutants are deficient in activation of this inflammasome (Koo et al 2008;Kurenuma et al 2009;Wong and Jacobs 2011;Abdalla et al 2012;Dorhoi et al 2012). The activation of NLRP3 inflammasome in Mtb-infected cells is dependent on the tyrosine kinase Syk, and this activation is essential for cell lysis, hence showing a necroptotic host cell death pathway (Wong and Jacobs 2011) (Fig.…”

“…A functional ESX-1 system is also essential for full activation of the NLRP3-inflammasome after mycobacterial infection (Koo et al 2008;Mayer-Barber et al 2010;McElvania Tekippe et al 2010;Mishra et al 2010;Walter et al 2010;Abdalla et al 2012;Dorhoi et al 2012). One report shows that this activation of NLRP3 leads to the induction of necroptosis (Wong and Jacobs 2011).…”