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Microbes & Immunity Host receptors in immunogenic cell death

signaling cascade. On the other hand, LPS is detected by immune responses, including antiviral immunity and
endosome-localized TLR4, activating TRIF-mediated autoimmunity. Understanding the specific roles of these
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IRF3/7 phosphorylation. The activation of both NF-κB RLRs in immune cells is crucial for developing targeted
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and IRF3/7 promotes the expression of type I interferons therapies that balance protection against infections with
(IFN-I) as well as pro-inflammatory cytokines, ultimately minimizing autoimmune damage. 41
recruiting and activating other immune cells to eradicate
infections. 29 2.3. NOD-like receptors as intracellular sensors
NLRs are a class of intracellular PRRs that have piqued
2.2. Recognition of nucleic acids by RIG-I-like the interest of researchers because of their essential roles
receptors
in recognizing bacteria that replicate intracellularly.
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Beyond the recognition of outer membrane components of Being evolutionarily conserved proteins found in both
pathogens, the host innate immune system also monitors the vertebrates and invertebrates, NLRs are characterized by
inner portions of these intruding bacteria that are released an N-terminal caspase recruitment domain (CARD), a
into host cells during infections, including their nucleic central NOD domain, and a C-terminal LRR domain. They
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acids RNA and DNA. RLRs are responsible for detecting are activated by a range of PAMPs, including flagellin, LPS,
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exogenous RNA from both viral and bacterial infections, such and components derived from bacterial peptidoglycan.
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as their double-stranded RNA (dsRNA), 5’-triphosphate Members of the NLR family include neuronal apoptosis
RNA, and short dsRNA. For instance, RIG-I recognizes inhibitory protein (NAIP), NOD1/2, NLRC3/4/5, and
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RNA fragments produced by Listeria monocytogenes and NLRP1/3/6/12: (1) NAIP5, a member of the NAIP family,
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Mycobacterium tuberculosis, subsequently triggering the was initially characterized for its capacity to detect flagellin
activation of the inflammasome and facilitating IFN-β originating from Legionella pneumophila. Macrophages
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production. It is worth mentioning that dsRNAs are not derived from mice with multiple polymorphisms in
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exclusively recognized by RLRs, but also by other receptor the Naip5 gene display increased susceptibility to
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types such as TLR3. 33,34 This led to the discovery of newly L. pneumophila infections. (2) NOD1 and NOD2 are
defined TLR3 agonists as an effective adjuvant for vaccines, specialized in the detection of numerous components from
especially against intracellular pathogens. 35 pathogenic bacteria. NOD1 senses diaminopimelic acid
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Exogenous cytosolic DNA derived from bacteria from Gram-negative bacteria, such as Shigella flexneri and P.
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is also sensed by the host’s receptors. These receptors aeruginosa. NOD2 recognizes muramyl dipeptide found
include the DNA-dependent activator of IFN-regulatory in both Gram-positive and -negative bacterial species,
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factors (DAI), the cyclic GMP-AMP synthase (cGAS)- including M. tuberculosis and Listeria monocytogenes. (3)
stimulator of interferon genes (STING) pathway, TLR9 Besides, the lethal toxin produced by Bacillus anthracis
and absent in melanoma 2 (AIM2). (1) DAI, the first is recognized by NLRP1b, culminating in its cleavage
2
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identified cytoplasmic DNA sensor, exhibits a high affinity and subsequent activation of inflammasomes. (4)
for DNA, thereby facilitating a robust immune response Additional ligands detected by NLRs encompass bacterial
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upon binding. (2) Furthermore, the cGAS-STING peptidoglycan and diminished levels of cytosolic ATP.
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pathway operates through a distinct mechanism. Upon Upon activation, NLRs undergo a conformational
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detecting the presence of foreign DNA, cGAS generates change, allowing them to oligomerize through CARD-
the secondary messenger cyclic GMP-AMP (cGAMP), CARD interactions. This connection further recruits
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which subsequently interacts with STING, instigating the an adaptor protein and a procaspase, assembling the
production of IFN-I. (3) The TLR9 receptor specifically multimeric protein complex, inflammasome, whose
recognizes unmethylated CpG motifs, which are prevalent activation culminates in the secretion of pro-inflammatory
in bacterial DNA. (4) AIM2 is adept at recognizing cytokines IL-1β and IL-18 or the induction of pyroptotic
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cytosolic dsDNA from bacterial infections. Upon dsDNA cell death. Collectively, these receptor systems provide a
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binding, AIM2 partners with the adaptor apoptosis- comprehensive defense mechanism, allowing the host to
associated Speck-like protein containing a CARD (ASC) detect and respond to invading pathogens effectively. As
and procaspase-1, leading to the activation of caspase-1 key players in initiating and regulating these cell death
and the release of pro-inflammatory cytokines interleukin pathways, NLRs have been increasingly investigated
(IL)-1β and IL-18. Similar to TLR, SNPs in TLR gene as important targets for both protective immunity and
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are also linked with disease susceptibility, including controlling excessive inflammation, such as the cytokine
viral infections and autoimmune diseases. Studies in storm seen in severe COVID-19 cases. Despite extensive
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novel mouse models expressing human-equivalent SNPs research, further studies are needed to understand NLRs’
have provided insights into how these variants influence roles in drug resistance and adaptive immunity. 53,54
Volume 1 Issue 2 (2024) 32 doi: 10.36922/mi.4264