Fig. 2 | Cellular & Molecular Immunology

Fig. 2

From: Molecular mechanisms and regulation of inflammasome activation and signaling: sensing of pathogens and damage molecular patterns

Fig. 2The alt text for this image may have been generated using AI.

The NLRP3 inflammasome. The NLRP3 inflammasome can be activated via canonical or noncanonical pathways. Canonical NLRP3 activation occurs in a two-step process. The first step, known as priming, is triggered by several classes of receptors in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The activation of priming receptors stimulates nuclear factor (NF)-κB signaling, resulting in the transcriptional upregulation of NLRP3 and proinflammatory cytokines, including pro-IL-1β. In addition, the priming step promotes posttranslational modifications (PTMs) of NLRP3 to maintain it in a poised state. The second step, or activation, is driven by diverse stimuli, including microbial products, environmental irritants, and cellular stressors, that induce cellular perturbations such as potassium (K+) efflux, calcium (Ca2+) influx, lysosomal disruption, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. For example, extracellular ATP binds the P2X7 receptor, affecting TWIK2 channels to mediate K+ efflux. Ca2+ influx is triggered via the calcium-sensing receptor (CASR), which in turn reduces the level of intracellular cyclic AMP (cAMP), relieving the inhibitory effect of cAMP on NLRP3. Mitochondrial damage results in the release of mitochondrial DNA, reactive oxygen species (ROS), and thioredoxin-interacting protein (TXNIP), all of which contribute to NLRP3 activation. ER stress exacerbates mitochondrial dysfunction to facilitate NLRP3 activation. The translocation of the cholesterol transcription factor and its chaperone, the SCAP–SREBP2 complex, from the ER to the Golgi apparatus under stress promotes NLRP3 activation. Moreover, protein kinase D can phosphorylate Golgi-bound NLRP3, facilitating its release and activation. Disruption of lysosomes leads to the release of cathepsin B, which can also activate NLRP3. Upon activation, NLRP3 binds to NIMA-related kinase (NEK) 7, which stabilizes the active conformation of NLRP3 and facilitates its oligomerization. Activated NLRP3 then recruits the adaptor protein ASC, which in turn binds with caspase-1 to form the functional inflammasome complex

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