Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury

Li, Yong; Huang, Xuan; Huang, Shengping; He, Hui; Lei, Tianhua; Saaoud, Fatma; Yu, Xiao‐Qiang; Melnick, Ari; Kumar, Anil; Papasian, Christopher J.; Fan, Daping; Fu, Mingui

doi:10.1038/sigtrans.2017.66

Cited by 52 publications

(65 citation statements)

References 51 publications

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“…In turn, we showed that MCPIP1 negatively regulates adipogenesis by degrading transcripts coding for C/EBPβ [13,15]. Observations made by Li et al were similar to ours, demonstrating that transcripts coding for C/EBPβ and C/EBPδ are direct targets of MCPIP1 RNase [36].…”

Section: Discussionsupporting

confidence: 89%

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Losko

Dolicka

Pydyn

et al. 2019

Cell. Mol. Life Sci.

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Obesity is considered a serious chronic disease, associated with an increased risk of developing cardiovascular diseases, non-alcoholic fatty liver disease and type 2 diabetes. Monocyte chemoattractant protein-1-induced protein-1 (MCPIP1) is an RNase decreasing stability of transcripts coding for inflammation-related proteins. In addition, MCPIP1 plays an important role in the regulation of adipogenesis in vitro by reducing the expression of key transcription factors, including C/EBPβ. To elucidate the role of MCPIP1 in adipocyte biology, we performed RNA-Seq and proteome analysis in 3T3-L1 adipocytes overexpressing wild-type ( WT MCPIP1) and the mutant form of MCPIP1 protein ( D141N MCPIP1). Our RNA-Seq analysis followed by confirmatory Q-RT-PCR revealed that elevated MCPIP1 levels in 3T3-L1 adipocytes upregulated transcripts encoding proteins involved in signal transmission and cellular remodeling and downregulated transcripts of factors involved in metabolism. These data are consistent with our proteomic analysis, which showed that MCPIP1 expressing adipocytes exhibit upregulation of proteins involved in cellular organization and movement and decreased levels of proteins involved in lipid and carbohydrate metabolism. Moreover, MCPIP1 adipocytes are characterized by decreased level of insulin receptor, reduced insulin-induced Akt phosphorylation, as well as depleted Glut4 level and impaired glucose uptake. Overexpression of Glut4 in 3T3-L1 cells expressed WT MCPIP1 rescued adipogenesis. Interestingly, we found decreased level of MCPIP1 along with an increase in body mass index in subcutaneous adipose tissue. The presented data show a novel role of MCPIP1 in modulating insulin sensitivity in adipocytes. Overall, our findings demonstrate that MCPIP1 is an important regulator of adipogenesis and adipocyte metabolism.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Discussionsupporting

confidence: 89%

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Losko

Dolicka

Pydyn

et al. 2019

Cell. Mol. Life Sci.

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“…Malt1 also has proteolytic (aka paracaspase) activity. Malt1 paracaspase activity may enhance NF‐κB activation, directly or indirectly (stabilizing target gene mRNAs), by cleaving substrates including Bcl10, A20, Regnase‐1, Roquin‐1, or Roquin‐2; alternatively, Malt1 can antagonize canonical NF‐κB signaling by cleaving substrates including NF‐κBp65, MCPIP1, and HOIL1 . Malt1 also plays a role in the activation innate immune cells.…”

Section: Introductionmentioning

confidence: 99%

Malt1 deficient mice develop osteoporosis independent of osteoclast-intrinsic effects of Malt1 deficiency

Monajemi

Fisk

Pang

et al. 2019

Journal of Leukocyte Biology

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This study tested the hypothesis that mucosa associated lymphoid tissue 1 (Malt1) deficiency causes osteoporosis in mice by increasing osteoclastogenesis and osteoclast activity. A patient with combined immunodeficiency (CID) caused by MALT1 deficiency had low bone mineral density resulting in multiple low impact fractures that was corrected by hematopoietic stem cell transplant (HSCT). We have reported that Malt1 deficient M s, another myeloid cell type, are hyper-responsive to inflammatory stimuli. Our objectives were to determine whether Malt1 deficient mice develop an osteoporosis-like phenotype and whether it was caused by Malt1 deficiency in osteoclasts. We found that Malt1 deficient mice had low bone volume by 12 weeks of age, which was primarily associated with reduced trabecular bone. Malt1 protein is expressed and active in osteoclasts and is induced by receptor activator of NF-B ligand (RANKL) in preosteoclasts. Malt1 deficiency did not impact osteoclast differentiation or activity in vitro. However, Malt1 deficient (Malt1 −/− ) mice had more osteoclasts in vivo and had lower levels of serum osteoprotegerin (OPG), an endogenous inhibitor of osteoclastogenesis. Inhibition of Malt1 activity in M s induced MCSF production, required for osteoclastogenesis, and decreased OPG production in response to inflammatory stimuli. In vitro, MCSF increased and OPG inhibited osteoclastogenesis, but effects were not enhanced in Malt1 deficient osteoclasts. These data support the hypothesis that Malt1 deficient mice develop an osteoporotic phenotype with increased osteoclastogenesis in vivo, but suggest that this is caused by inflammation rather than an effect of Malt1 deficiency in osteoclasts.

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“…During NFκB activation, MALT1 acts as an adaptor protein bridging CARD11 and BCL10 . However, MALT1 also has proteolytic activity and is known as “paracaspase.” Multiple MALT1 substrates have been identified; autoproteolysis and cleavage of BCL10, A20, Regnase‐1, Roquin‐1, and Roquin‐2 may enhance TCR‐mediated NFκB activation directly and indirectly, by stabilizing mRNAs of target genes, whereas cleavage of the NFκB subunit (p65), MCPIP1, and HOIL1 may inhibit canonical NFκB signaling . Thus, the effect of MALT1's paracaspase activity may complement or oppose its activity as a scaffolding protein.…”

Section: Introductionmentioning

confidence: 99%

Malt1 blocks IL-1β production by macrophages in vitro and limits dextran sodium sulfate-induced intestinal inflammation in vivo

Monajemi

Pang

Bjornson

et al. 2018

Journal of Leukocyte Biology

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This study tested the hypothesis that Malt1 deficiency in macrophages contributes to dextran sodium sulfate (DSS)-induced intestinal inflammation in Malt1-deficient mice. In people, combined immunodeficiency caused by a homozygous mutation in the MALT1 gene is associated with increased susceptibility to bacterial infections and chronic inflammation, including severe inflammation along the gastrointestinal tract. The consequences of Malt1 deficiency have largely been attributed to its role in lymphocytes, but Malt1 is also expressed in macrophages, where it is activated downstream of TLR4 and dectin-1. The effect of Malt1 deficiency in murine macrophages and its contribution to DSS-induced colitis have not been investigated. Our objectives were to compare the susceptibility of Malt1 and Malt1 mice to DSS-induced colitis, to determine the contribution of macrophages to DSS-induced colitis in Malt1 mice, and to assess the effect of innate immune stimuli on Malt1 macrophage inflammatory responses. We found that Malt1 deficiency exacerbates DSS-induced colitis in mice, accompanied by higher levels of IL-1β, and that macrophages and IL-1 signaling contribute to pathology in Malt1 mice. Malt1 macrophages produce more IL-1β in response to either TLR4 or dectin-1 ligation, whereas inhibition of Malt1 proteolytic (paracaspase) activity blocked IL-1β production. TLR4 or dectin-1 stimulation induced Malt1 protein levels but decreased its paracaspase activity. Taken together, these data support the hypothesis that Malt1 macrophages contribute to increased susceptibility of Malt1 mice to DSS-induced colitis, which is dependent on IL-1 signaling. Increased IL-1β production by MALT1-deficient macrophages may also contribute to chronic inflammation in people deficient in MALT1.

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Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury

Cited by 52 publications

References 51 publications

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Integrative genomics reveal a role for MCPIP1 in adipogenesis and adipocyte metabolism

Malt1 deficient mice develop osteoporosis independent of osteoclast-intrinsic effects of Malt1 deficiency

Malt1 blocks IL-1β production by macrophages in vitro and limits dextran sodium sulfate-induced intestinal inflammation in vivo

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