Dataset Information

Receptor-Interacting Protein 140 Orchestrates the Dynamics of Macrophage M1/M2 Polarization.

ABSTRACT: Macrophage classical (M1) versus alternative (M2) polarization is critical for the homeostatic control of innate immunity. Uncontrolled macrophage polarization is frequently implicated in diseases. This study reports a new functional role for receptor-interacting protein 140 (RIP140) in regulating this phenotypic switch. RIP140 is required for M1 activation, and its degradation is critical to LPS-induced endotoxin tolerance (ET). Here, we found that failure to establish RIP140 degradation-mediated ET prevents M2 polarization, and reducing RIP140 level facilitates an M1/M2 switch, resulting in more efficient wound healing in animal models generated with either transgenic or bone marrow transplant procedures. The M2-suppressive effect is elicited by a new function of RIP140 that, in macrophages exposed to M2 cues, is exported to cytosol, forming complexes with CAPNS1 (calpain regulatory subunit) to activate calpain 1/2, that activates PTP1B phosphatase. The activated PTP1B then reduces STAT6 phosphorylation, thereby suppressing the efficiency of M2 polarization. It is concluded that RIP140 plays dual roles in regulating the M1-M2 phenotype switch: the first, in the nucleus, is an M1 enhancer and the second, in the cytosol, is an M2 suppressor. Modulating the level and/or subcellular distribution of RIP140 can be a new therapeutic strategy for diseases where inflammatory/anti-inflammatory responses are critical.

SUBMITTER: Lin YW

PROVIDER: S-EPMC5105833 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Receptor-Interacting Protein 140 Orchestrates the Dynamics of Macrophage M1/M2 Polarization.

Lin Yi-Wei YW Lee Bomi B Liu Pu-Ste PS Wei Li-Na LN

Journal of innate immunity 20150723 1

Macrophage classical (M1) versus alternative (M2) polarization is critical for the homeostatic control of innate immunity. Uncontrolled macrophage polarization is frequently implicated in diseases. This study reports a new functional role for receptor-interacting protein 140 (RIP140) in regulating this phenotypic switch. RIP140 is required for M1 activation, and its degradation is critical to LPS-induced endotoxin tolerance (ET). Here, we found that failure to establish RIP140 degradation-mediat ...[more]

PMID: 26228026

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Project description:Macrophages belong to a special phagocytic subgroup of human leukocytes and are one of the important cells of the human immune system. Small noncoding RNAs are a group of small RNA molecules that can be transcribed without the ability to encode proteins but could play a specific function in cells. SncRNAs mainly include microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), small nuclear RNAs (snRNAs) and repeat RNAs. We used high-throughput sequencing analysis and qPCR to detect the expression changes of the small noncoding RNAome during macrophage polarization. Our results showed that 84 miRNAs and 47 miRNAs with were downregulated during M1 macrophage polarization and that 11 miRNAs were upregulated and 19 miRNAs were downregulated during M2 macrophage polarization. MiR-novel-3-nature and miR-27b-5p could promote expression of TNF-α which was marker gene of M1 macrophages. The piRNA analysis results showed that 69 piRNAs were upregulated and 61 piRNAs were downregulated during M1 macrophage polarization and that 3 piRNAs were upregulated and 10 piRNAs were downregulated during M2 macrophage polarization. DQ551351 and DQ551308 could promote the mRNA expression of TNF-α and DQ551351overexpression promoted the antitumor activity of M1 macrophages. SnoRNA results showed that 62 snoRNAs were upregulated and 59 snoRNAs were downregulated during M1 macrophage polarization, whereas 6 snoRNAs were upregulated and 10 snoRNAs were downregulated during M2 macrophage polarization. Overexpression of snoRNA ENSMUST00000158683.2 could inhibit expression of TNF-α. For snRNA, we found that 12 snRNAs were upregulated and 15 snRNAs were downregulated during M1 macrophage polarization and that 2 snRNAs were upregulated during M2 macrophage polarization. ENSMUSG00000096786 could promote expression of IL-1 and iNOS and ENSMUSG00000096786 overexpression promoted the antitumor activity of M1 macrophages. Analysis of repeat RNAs showed that 7 repeat RNAs were upregulated and 9 repeat RNAs were downregulated during M1 macrophage polarization and that 2 repeat RNAs were downregulated during M2 macrophage polarization. We first reported the expression changes of piRNA, snoRNA, snRNA and repeat RNA during macrophage polarization, and preliminarily confirmed that piRNA, snoRNA and snRNA can regulate the function of macrophages.

Project description:Macrophage polarization plays essential and diverse roles in most diseases, such as atherosclerosis, adipose tissue inflammation, and insulin resistance. Homeostasis dysfunction in M1/M2 macrophage polarization causes pathological conditions and inflammation. Neuroinflammation is characterized by microglial activation and the concomitant production of pro-inflammatory cytokines, leading to numerous neurodegenerative diseases and psychiatric disorders. Decreased neuroinflammation can be obtained by using natural compounds, including flavonoids, which are known to ameliorate inflammatory responses. Among flavonoids, quercetin possesses multiple pharmacological applications and regulates several biological activities. In the present study, we found that quercetin effectively inhibited the expression of lipocalin-2 in both macrophages and microglial cells stimulated by lipopolysaccharides (LPS). The production of nitric oxide (NO) and expression levels of the pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, were also attenuated by quercetin treatment. Our results also showed that quercetin significantly reduced the expression levels of the M1 markers, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β, in the macrophages and microglia. The M1 polarization-associated chemokines, C-C motif chemokine ligand (CCL)-2 and C-X-C motif chemokine ligand (CXCL)-10, were also effectively reduced by the quercetin treatment. In addition, quercetin markedly reduced the production of various reactive oxygen species (ROS) in the microglia. The microglial phagocytic ability induced by the LPS was also effectively reduced by the quercetin treatment. Importantly, the quercetin increased the expression levels of the M2 marker, IL-10, and the endogenous antioxidants, heme oxygenase (HO)-1, glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), and NAD(P)H quinone oxidoreductase-1 (NQO1). The enhancement of the M2 markers and endogenous antioxidants by quercetin was activated by the AMP-activated protein kinase (AMPK) and Akt signaling pathways. Together, our study reported that the quercetin inhibited the effects of M1 polarization, including neuroinflammatory responses, ROS production, and phagocytosis. Moreover, the quercetin enhanced the M2 macrophage polarization and endogenous antioxidant expression in both macrophages and microglia. Our findings provide valuable information that quercetin may act as a potential drug for the treatment of diseases related to inflammatory disorders in the central nervous system.

Dataset Information

Receptor-Interacting Protein 140 Orchestrates the Dynamics of Macrophage M1/M2 Polarization.

Publications

Receptor-Interacting Protein 140 Orchestrates the Dynamics of Macrophage M1/M2 Polarization.

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