The activation of NLRP3-inflammsome by stimulation of diesel exhaust particles in lung tissues from emphysema model and RAW 264.7 cell line

Abstract

Background/AimsDiesel exhaust particles (DEPs) lead to elevation of reactive oxygen species, which can activate the nucleotide-binding oligomerization domain-like receptor (NLR) family members containing the pyrin domain 3 (NLRP3)-inf lammasome. In this study, we elucidated whether NLRP3 -inf lammasome is activated by DEPs and whether antioxidants (N-acetylcysteine [NAC]) could inhibit such activation.MethodsRAW 264.7 cells and ex vivo lung tissues explants obtained from elastase-induced emphysema animal models were stimulated with cigarette smoking extract (CSE), DEPs, and lipopolysaccharide, and levels of interleukin-1β (IL-1β), caspase-1 and nucleotide-binding oligomerization domain-like receptor (NLR) family members containing the pyrin domain (NLRP3)-inflammasome were assessed by Western blotting and immunohistochemistry.ResultsNAC and caspase-1 inhibitor suppressed CSE- and DEP-induced secretion of IL-1β in RAW 264.7 cells. The expression levels of the NLRP3-inflammasome and caspase-1 were upregulated in RAW 264.7 cells by stimulation with CSE and DEPs and were inhibited by NAC. CSE and DEPs increased the secretion of IL-1β in lung tissues from both the normal and elastase-induced emphysema groups. The secretion of IL-1β by CSE and DEPs was increased in the elastin-induced emphysema group more than that in the normal group (CSE: 309 ± 19 pg/mL vs. 151 ± 13 pg/mL, respectively, p < 0.05; DEP: 350 ± 24 pg/mL vs. 281 ± 15 pg/mL, respectively, p < 0.05). NAC inhibited CSE- and DEP-induced IL-1β secretion in both the normal and elastase-induced emphysema groups. NLRP3-inflammasome expression as determined by immunohistochemistry was increased by CSE and DEPs in both the normal and elastin-induced emphysema groups, and was suppressed by NAC.ConclusionsThe NLRP3-inf lammasome is activated by DEPs in ex vivo tissue explants from elastase-induced emphysema animal model, and this activation is inhibited by NAC.

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“…Activation of the NLRP3 inflammasome leads to caspase-1 activation, which switches pro-IL-1β to the matured IL-1β through a complex pathway. [158][159][160] In a number of F I G U R E 2 Cellular pathways whereby melatonin facilitates M2 macrophage polarization. A, Melatonin induces tyrosine phosphorylation of IRS and activation of GRB2, thereby promoting tyrosine phosphorylation and homodimerization of STAT-6, which enhances M2 macrophage polarization through multiple mechanisms.…”

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“…Interestingly, local airway NLRP3 inflammasome activation is positively correlated with acute exacerbations and lower airway microbial colonization in COPD patients ( 103 , 104 ). Moreover, in an elastase-induced emphysema model, the NLRP3 inflammasome is activated in addition to hyperproduction of mucin MUC5AC by diesel extract particles, extracellular ATP, and inflammatory protein S100 ( 105 , 106 ).…”

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“… 30 , 31 The same responses could be triggered by co-exposure of DEP with a low level of soybean allergen. 32 …”