Abstract
Inflammasomes are multiprotein complexes nucleating around an NLR (Nucleotide-binding domain and Leucine-rich Repeat containing protein), which regulate the secretion of the pro-inflammatory interleukin (IL)-1β and IL-18 cytokines. Monocytes and macrophages, the main cells expressing the inflammasome genes, adapt to their surrounding microenvironment by a phenotypic polarization towards a pro-inflammatory M1 phenotype that promotes inflammation or an anti-inflammatory M2 phenotype important for resolution of inflammation. Despite the importance of inflammasomes in health and disease, little is known about inflammasome gene expression in relevant human cells and the impact of monocyte and macrophage polarization in inflammasome gene expression. We examined the expression of several members of the NLR, caspase and cytokine family, and we studied the activation of the well-described NLRP3 inflammasome in an experimental model of polarized human primary monocytes and monocyte-derived macrophages (M1/M2 phenotypes) before and after activation with LPS, a well-characterized microbial pattern used in inflammasome activation studies. Our results show that the differentiation of monocytes to macrophages alters NLR expression. Polarization using IFN-γ (M1 phenotype), induces among the NLRs studied, only the expression of NOD2. One of the key results of our study is that the induction of NLRP3 expression by LPS is inhibited in the presence of IL-4+IL-13 (M2 phenotype) at both mRNA and protein level in monocytes and macrophages. Unlike caspase-3, the expression of inflammasome-related CASP1 (encodes caspase-1) and CASP4 (encodes caspase-4) is up-regulated in M1 but not in M2 cells. Interestingly, the presence of LPS marginally influenced IL18 mRNA expression and secretion, unlike its impact on IL1B. Our data provide the basis for a better understanding of the role of different inflammasomes within a given environment (M1 and M2) in human cells and their impact in the pathophysiology of several important inflammatory disorders.
Highlights
Inflammation is characterized by increased cytokine secretion and activation of innate immunity cells
The NLRP3 inflammasome gained a lot of attention due to the causality of NLRP3 mutations in cryopyrin-associated periodic syndromes (CAPS) [21,22], an auto-inflammatory pathology characterized by high levels of IL-1β secretion from peripheral blood mononuclear cells (PBMCs) of patients
We initially studied the mRNA expression of different Nucleotide-binding domain and leucine-rich repeat containing proteins (NLR) genes in human PBMC, monocytes and macrophages
Summary
Inflammation is characterized by increased cytokine secretion and activation of innate immunity cells. M1 cells play an important role in host defense through cytokine production, whereas M2 cells mediate tissue repair and homeostasis [1,2,3,4,5,6]. This adaptation of monocytes and macrophages to their immediate microenvironment is known as polarization and can occur at any time during inflammation [7]. Innate response during inflammation is assured by the family of the evolutionarily conserved NLR receptors (Nucleotide-binding domain and Leucine-rich Repeat containing proteins) expressed mainly in monocytes and macrophages [8]. The NLRP3 inflammasome gained a lot of attention due to the causality of NLRP3 mutations in cryopyrin-associated periodic syndromes (CAPS) [21,22], an auto-inflammatory pathology characterized by high levels of IL-1β secretion from peripheral blood mononuclear cells (PBMCs) of patients
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