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.

Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

“…Additionally, if NF-κB activation is inhibited in Mϕ, they acquire an anti-inflammatory phenotype and suppress renal injury when transferred it in a rat model of nephrotoxic nephritis [96]. Conversely, NLRP3 is also involved in M2 polarization since NLRP3 transactivate IL-4 promoter to increase IL-4 expression (characteristic of M2 phenotype) in peripheral blood monocyte-derived Mϕ [97]. In addition, it has been found in UUO mice that NLRP3 inflammasome activates NF-κB and IL-4/STAT6 signaling pathways and promotes M1 and M2 macrophage infiltration and renal injury [98].…”

The Role of T Cells and Macrophages in Asthma Pathogenesis: A New Perspective on Mutual Crosstalk

“…Furthermore, they demonstrated that allergen-induced disease was exacerbated after the adoptive transfer of M2 macrophages [ 82 ]. NOD-, LRR-, and pyrin domain-containing (NLRP) 3 inflammasome was proved to have the potential to upregulate IL-4 to promote M2 polarization [ 83 ]. Specifically, IL-4 or IL-13 induces M2a macrophages to express IL-10, TGF- β , and chemokines (CCL17, CCL18, CCL22, and CCL24), which participate in Th2-type inflammation, airway remodeling, and parasite immunomodulation.…”

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…Non-classical monocytes are suggested to be the source of wound healing macrophages [143], although the contribution of CD16 + monocytes in a steady state to the macrophage population is unclear [144]. Furthermore, these two macrophage phenotypes (M1 and M2) are regarded as being transient and occurring along a spectrum [145,146], and several other factors seem to influence or drive monocyte-derived macrophage polarisation, including platelets [147], IL-4 [148], and microRNA [146].…”