Fig. 1.

Possible molecular mechanisms involved in aberrant inflammatory response to severe acute respiratory syndrome coronavirus 2 in frail patients. The binding of severe acute respiratory syndrome coronavirus 2 to angiotensin-converting enzyme 2 and its interaction with intracellular toll-like receptors (TLRs) triggers a sequence of responses, which leads to nuclear factor kappa B activation and interleukin synthesis. Host cell inflammation could be exacerbated by NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and proinflammatory cytokine production. NLRP3 inflammasome activation requires 2 steps generated by stressful conditions: Transcription of NLRP3 and adaptor protein apoptosis-associated speck-like protein-containing CARD adapter, pro-caspase-1, and their assembly and activation. The first step is consequent to nuclear factor kappa B activation and translocation into the nucleus, stimulated by lipopolysaccharide–TLR4 binding through c-Jun N-terminal kinase and IκB kinase intracellular signaling. The second step is induced by an abnormal mitochondrial reactive oxygen species production, or by pathogen-associated molecular patterns, damage-associated molecular patterns, and microbial-associated molecular pattern stimuli related to gut dysbiosis. Moreover, the K⁺ outflow, due to adenosine triphosphate extracellular stimulus, or intracellular and cytosolic Ca²⁺ fluxes imbalance induces NLRP3 inflammasome assembly. NLRP3 activation is also regulated by AngII overexpression stimulated by lipopolysaccharide–TRL4 interaction and gut dysbiosis-derived metabolite trimethylamine N-oxide.