NLRP3 regulates macrophage M2 polarization through up-regulation of IL-4 in asthma.

Abstract

Activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome received substantial attention recently in inflammatory diseases. Macrophages contribute to allergic inflammation in asthma. The present study was aimed to investigate the effect of NLRP3 inflammasome on the polarization of macrophages. We utilized human primary monocytes and monocyte-derived macrophages to study the expression of NLRP3 inflammasome components (NLRP3, apoptosis-associated specklike protein, and caspase-1) and its downstream cytokine interleukin-1β (IL-1β). By gain- or loss-of-function assays, we next explored the effects of NLRP3 inflammasome on M1/M2 polarization and secretion of IL-4, interferon-γ, tumor necrosis factor-α, and IL-1β. The results showed increased numbers of M2 cells in asthma. And NLRP3 inflammasome was activated and involved in the inflammation of asthma. Furthermore, silence of NLRP3 down-regulated IL-4 secretion and up-regulated M1/M2. In contrast, overexpression of NLRP3 increased IL-4 and decreased M1/M2. As expected, IL-4 was involved in NLRP3-mediated down-regulation of Ml/M2 ratio. Moreover, NLRP3 interacted with IRF4 and was required for optimal IRF4-dependent IL-4 transcription. Subsequently, deficiency of NLRP3 in ovalbumin-induced allergic asthmatic mice impaired lung inflammation and up-regulated M1/M2, and diminished IL-4 in bronchoalveolar lavage fluid. Collectively, we demonstrated here that activation of NLRP3 was engaged in the promotion of asthma. NLRP3, but not the inflammasome adaptor ASC or caspase-1, promoted the polarization of M2 macrophages through up-regulating the expression of IL-4, thereby contributing to its regulation of asthma.

• Authors: Ying Liu, Xin Gao, Yi Miao, Yuanyuan Wang, Huan Wang, Zhe Cheng, Xi Wang, Xiaogang Jing, Liuqun Jia, Lingling Dai, Meng Liu, Lin An
• Journal: The Biochemical journal (Biochem J) Vol. 475 Issue 12 Pg. 1995-2008 (06 21 2018) ISSN: 1470-8728 [Electronic] England
• PMID: 29626160 (Publication Type: Journal Article)
• Copyright: © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• IL4 protein, human
• Inflammasomes
• Interferon Regulatory Factors
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• interferon regulatory factor-4
• Interleukin-4
• Caspase 1

Topics

• Asthma (metabolism, pathology)
• Caspase 1 (metabolism)
• Humans
• Inflammasomes (metabolism)
• Interferon Regulatory Factors (metabolism)
• Interleukin-4 (biosynthesis)
• Macrophages (metabolism, pathology)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Up-Regulation