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TLR2 activation induces antioxidant defence in human monocyte-macrophage cell line models.

ABSTRACT: When monocytes are recruited to inflammation/infection sites, extravasate and differentiate into macrophages, they encounter increasing levels of oxidative stress, both from exogenous and endogenous sources. In this study, we aimed to determine whether there are specific biochemical mechanisms responsible for an increase in oxidative stress resistance in differentiating macrophages. We performed experiments on in vitro cell line models of the monocyte-macrophage differentiation axis (less differentiated THP-1 cells and more differentiated Mono Mac 6 cells). At the same time, we verified the hypothesis that activating monocyte/macrophage innate immune response by pathogens (exemplified by stimulating the TLR2 pattern recognition receptor) would further strengthen cellular antioxidant defences. We found that resistance to exogenous oxidative stress increased substantially both during differentiation and upon activation of TLR2. This increase in antioxidant resistance was accompanied by decrease in free radical damage to cellular proteins. On the molecular level, this resistance was mediated especially by increased levels and activity of glutathione, glutathione-related antioxidant enzymes and Mn superoxide dismutase, as shown by gene expression assays, Western blotting and enzyme activity assays. Moreover, upon TLR2 activation additional molecular mechanisms came into play, conferring additional resistance levels even upon differentiated macrophage-like cells, mainly related to thioredoxin-linked antioxidant enzymes.

SUBMITTER: Karwaciak I

PROVIDER: S-EPMC5589577 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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TLR2 activation induces antioxidant defence in human monocyte-macrophage cell line models.

Karwaciak Iwona I Gorzkiewicz Michal M Bartosz Grzegorz G Pulaski Lukasz L

Oncotarget 20170421 33

When monocytes are recruited to inflammation/infection sites, extravasate and differentiate into macrophages, they encounter increasing levels of oxidative stress, both from exogenous and endogenous sources. In this study, we aimed to determine whether there are specific biochemical mechanisms responsible for an increase in oxidative stress resistance in differentiating macrophages. We performed experiments on <i>in vitro</i> cell line models of the monocyte-macrophage differentiation axis (less ...[more]

PMID: 28903338

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Project description: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.

Dataset Information

TLR2 activation induces antioxidant defence in human monocyte-macrophage cell line models.

Publications

TLR2 activation induces antioxidant defence in human monocyte-macrophage cell line models.

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