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Microbes & Immunity Host receptors in immunogenic cell death

2.4. Mechanism of inflammasome activation then recruits pro-caspase-1 to form the inflammasome
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The inflammasome is a multi-protein complex assembled complex. Certain bacteria encode effectors that allow
on detection of PAMPs by PRRs, in the process of them to escape detection by the AIM2 inflammasome. L.
orchestrating host defenses. It typically constitutes a pneumophila, for instance, employs SdhA to maintain the
nucleotide-binding domain and LRR-containing protein, integrity of the bacterial replicative vacuole, preventing
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the adaptor protein ASC, and pro-caspases. Two signals the leakage of DNA into the cytoplasm. (4) Finally,
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are required for the inflammasome to be activated. The recent investigations have unveiled a unique mechanism
first signal is priming, which involves the recognition of employed by the pyrin inflammasome to identify bacterial
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PAMPs by membrane-bound or cytoplasmic PRRs. This infections. In this context, pyrin recognizes the bacterial-
causes the upregulation of pro-IL-1 and pro-IL-18. The induced modifications of Rho GTPases, such as the
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second signal is provided by the inflammasome complex glycosylation by Clostridium difficile toxins TcdA/B and
itself, which triggers the oligomerization of NLRs and the the mono ADP-ribosylation by the C3 exoenzyme from
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recruitment of ASC and pro-caspase-1. This complex Clostridium botulinum. Additional bacteria-induced
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then undergoes a conformational change that results in the modifications, including adenylation and deamidation,
activation of caspase-1 and the processing of pro-IL-1β and also serve as initiating stimuli for the activation of the
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pro-IL-18 into their mature biologically active forms. 56,57 pyrin inflammasome.
The coordinated interplay of these sequential processes The activation of inflammasomes subsequent to the
ultimately facilitates the activation of immune responses detection of PAMPs by PRRs culminates in an enhanced
and the efficient elimination of invasive pathogens. 58,59 immune response through the proteolytic processing and
subsequent release of pro-inflammatory cytokines, notably
Many varieties of inflammasomes have been identified 73
so far; each is activated by specific stimuli and composed IL-1β and IL-18. These cytokines play a crucial role in
of diverse members of the NLR family and caspase orchestrating the inflammatory cascade, inducing pyrexia,
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effectors: (1) The NLRP3 inflammasome, comprising and mobilizing immune cells to the site of infection.
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the receptor NLRP3, adaptor protein ASC, and pro- While this inflammatory response is indispensable
caspase-1, represents the most extensively analyzed for the containment and eradication of pathogens, it
inflammasome assembly. Its activation can be triggered necessitates precise regulation to mitigate the risk of
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by a broad spectrum of PAMPs, including bacterial RNA, hyperinflammation, which may precipitate tissue injury,
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DNA viruses, and fungi. 61,62 The priming for canonical autoinflammation, or systemic sepsis. Moreover, in
NLRP3 inflammasome activation is mediated by caspase-8 instances where the pathogenic onslaught surpasses the
whereas non-canonical NLRP3 inflammasome activation host’s defensive capabilities, infected cells may resort to
requires the binding of caspase-11 and cytosolic LPS. immunogenic cell death mechanisms as a fail-safe to
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Recent studies have elucidated the pivotal role of the impede further microbial propagation. The intricate
NLRP3 inflammasome in mediating the proinflammatory interplay between infection-triggered immunogenic cell
response characteristic of chronic liver diseases, including death and host-pathogen dynamics warrants a detailed
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ALD and NAFLD. Its central involvement in the exploration, which will be elucidated in the subsequent
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pathogenesis of these conditions highlights the potential discourse.
for therapeutic interventions aimed at modulating 3. Immunogenic cell death triggered by the
inflammasome components or the cytokines they pathogen infections
generate. (2) Another important inflammasome is the
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NAIP-NLRC4 inflammasome, which can be activated One effective strategy of host immune defense in response
by cytosolic bacterial flagellin and needle proteins, inner to the infection of pathogens is the induction of cell
rod proteins of the type III secretion system (T3SS) of death, an event that will eliminate the niche for pathogen
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pathogenic bacteria. Interestingly, proteins involved in propagation. Investigation of host responses including cell
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cellular metabolic pathways, which are subject to caspase- death triggered by pathogens has led to the identification
1-mediated cleavage during infection with Salmonella of PRRs and novel immune mechanisms. The dynamic
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Typhimurium, also instigate the activation of the NLR interaction between PAMPs and host germline-encoded
family CARD domain-containing protein 4 (NLRC4) pattern-recognition receptors empowers the host to
inflammasome. (3) AIM2 inflammasome plays a distinguish self-entities from foreign pathogens and to
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critical role in sensing cytosolic dsDNA from invading efficiently eradicate pathogens. Despite the immense
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bacteria. Structural analyses reveal that upon binding diversity in the microbial constitution, the host is
to dsDNA, AIM2 oligomerizes and recruits ASC, which nonetheless able to distinguish them through a small
Volume 1 Issue 2 (2024) 33 doi: 10.36922/mi.4264