Mercury and arsenic attenuate canonical and non-canonical NLRP3 inflammasome activation

Abstract

Exposure to heavy metals can cause several diseases associated with the immune system. Although the effects of heavy metals on production of inflammatory cytokines have been previously studied, the role of heavy metals in inflammasome activation remains poorly studied. The inflammasome is an intracellular multi-protein complex that detects intracellular danger signals, resulting in inflammatory responses such as cytokine maturation and pyroptosis. In this study, we elucidated the effects of four heavy metals, including cadmium (Cd), mercury (Hg), arsenic (As), and lead (Pb), on the activation of NLRP3, NLRC4, and AIM2 inflammasomes. In our results, mercury and arsenic inhibited interleukin (IL)-1β and IL-18 secretion resulting from canonical and non-canonical NLRP3 inflammasome activation in macrophages and attenuated elevation of serum IL-1β in response to LPS treatment in mice. In the mechanical studies, mercury interrupted production of mitochondrial reactive oxygen species, release of mitochondrial DNA, and activity of recombinant caspase-1, whereas arsenic down-regulated expression of promyelocytic leukemia protein. Both mercury and arsenic inhibited Asc pyroptosome formation and gasdermin D cleavage. Thus, we suggest that exposure to mercury and/or arsenic could disrupt inflammasome-mediated inflammatory responses, which might cause unexpected side effects.

Exogenous carbon monoxide protects against mitochondrial DNA‑induced hippocampal pyroptosis in a model of hemorrhagic shock and resuscitation

“…NLRP3 inflammasome activation is a multistep process that includes assembly of ASc and pro-caspase-1 (25). mtdNA from injured mitochondria has been reported to be fused in response to NLRP3 inflammasome activation (26,27). The results of the present study revealed that cORM-3 partially reversed the increase in mtdNA levels and the decreased mitochondrial integrity after HSR compared with icORM-3.…”

Polymorphism of nucleotide binding domain-like receptor protein 3 (NLRP3) increases susceptibility of total urinary arsenic to renal cell carcinoma

“…Another study demonstrated that arsenic enhanced the AIM2 inflammasome activation to increase IL-1 β/ IL-18 production 11 . In contrast, Ahn et al 15 demonstrated that arsenic could inhibit the activation of the NLRP3 inflammasome in macrophages in response to lipopolysaccharide treatment, which attenuated the elevation of serum IL-1β in mice. Animal and cell culture studies showed that arsenic trioxide and other arsenic compounds inhibited NLRP3 inflammasome, caspase-1, and IL-1β inflammatory signaling, and played a major role in its anti-cancer effects 43 .…”

“…One recent study reported that arsenic could activate the NLRP3 inflammasome and induce pyroptosis 14 . However, mercury and arsenic can inhibit interleukin (IL)-1β and IL-18 secretion, which is caused by the activation of both the classical and non-classical NLRP3 inflammasomes in macrophages, suggesting that exposure to these heavy metals could destroy the inflammasome-mediated immune responses and cause unexpected side effects 15 . Because of the inconsistency of these findings, the association between NLRP3 inflammasomes and arsenic exposure remains unclear.…”

Sodium para-aminosalicylic acid inhibits manganese-induced NLRP3 inflammasome-dependent pyroptosis by inhibiting NF-κB pathway activation and oxidative stress

“…It is an essential source of pro-inflammatory factors and oxidative stress, such as TNF, interleukin and other neurotoxic substances [ 58 , 59 ]. Many studies showed that heavy metals could induce neurotoxicity via activating the microglial cells, especially Mn [ 22 , 23 , 62 ]. In vitro study demonstrated that Mn and/or LPS can activate BV2 cells via activating MAP kinase, PI3K/Akt pathways and inflammatory process [ 63 ].…”