Figure 9.

Mercury mediated regulation of Ca²⁺ mediated NLRP3 inflammasome in KD. NLRP3 inflammasome activation is a two-step process with priming and an activation signal. (A) Unstimulated APCs. (B) Signal one triggers a pattern recognition receptor on APCs such as Toll-like receptors (TLRs) to increase pro-IL-1β and proIL-18 via the NF-κB pathway. Signal two mediates the assembly and activation of the inflammasome, a large molecular platform composed of an NLR protein (such as NLRP3), the adaptor ASC and pro-inflammatory caspases (such as caspase 1). Activation of caspase 1 cleaves pro-IL-1β and pro-IL-18 into their respective active cytokines. The following steps illustrate the contribution of HgCl2 and ITPKC to the disease model: (C) 1. ITPKC regulates the phosphorylation of IP3 to IP4. Decreased ITPKC (knockout mice or humans with CC genotype) results in increased IP3, which binds to IP3R. 2. Release of intracellular Ca²⁺ from the endoplasmic reticulum (ER). (D) 3. Intracellular Ca²⁺ increases NLRP3 expression and inflammasome activation leading to 4. Increased production of IL-1β and IL-18 from their pro-forms. Mercury acts as signal 2, leading to increased intracellular Ca²⁺ and NLRP3 expression and activation, leading to step 4.