Bacterial Sensor Triggering Receptor Expressed on Myeloid Cells-2 Regulates the Mucosal Inflammatory Response

Correale, Carmen; Genua, Marco; Vetrano, Stefania; Mazzini, Elisa; Martinoli, Chiara; Spinelli, Antonino; Arena, Vincenzo; Peyrin-Biroulet, L; Caprioli, Flavio; Passini, Nadia; Panina–Bordignon, Paola; Repici, Alessandro; Malesci, Alberto; Rutella, Sergio; Rescigno, María; Danese, Silvio

doi:10.1053/j.gastro.2012.10.040

Cited by 51 publications

(67 citation statements)

References 32 publications

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“…Our findings indicate that TREM2 is involved in determining proinflammatory macrophage activation on contact with the malaria parasite, similar to the profile recently described in microglia cells (29). Indirect evidence suggests expression of TREM2 ligands by both yeast and bacteria (30), supporting a role for TREM2 as a pathogen sensor (31). Our results indicate that P. berghei sporozoites activate macrophages in a TREM2-dependent fashion, suggesting that Plasmodium expresses as-yet unidentified TREM2 ligands.…”

Section: Discussionsupporting

confidence: 85%

“…TREM2 has been shown to contribute to both inflammatory and phagocytic responses to infectious agents (31,32). Our in vitro experiments suggest that the triggering of TREM2 in macrophages is part of a decisive effector signal that enables a degree of control of parasite expansion inside hepatocytes, possibly by promoting killing/phagocytosis of infected hepatocytes and decreasing the yield of mature parasites.…”

Section: Discussionmentioning

confidence: 69%

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TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

Gonçalves

Rodrigues-Duarte

Rodo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Plasmodium liver stage infection is a target of interest for the treatment of and vaccination against malaria. Here we used forward genetics to search for mechanisms underlying natural host resistance to infection and identified triggering receptor expressed on myeloid cells 2 (TREM2) and MHC class II molecules as determinants of Plasmodium berghei liver stage infection in mice. Locus belr1 confers resistance to malaria liver stage infection. The use of newly derived subcongenic mouse lines allowed to map belr1 to a 4-Mb interval on mouse chromosome 17 that contains the Trem2 gene. We show that Trem2 expression in the nonparenchymal liver cells closely correlates with resistance to liver stage infection, implicating TREM2 as a mediator of the belr1 genetic effect. Trem2-deficient mice are more susceptible to liver stage infection than their WT counterparts. We found that Kupffer cells are the principle cells expressing TREM2 in the liver, and that Trem2 −/− Kupffer cells display altered functional activation on exposure to P. berghei sporozoites. TREM2 expression in Kupffer cells contributes to the limitation of parasite expansion in isolated hepatocytes in vitro, potentially explaining the increased susceptibility of Trem2 −/− mice to liver stage infection. The MHC locus was also found to control liver parasite burden, possibly owing to the expression of MHC class II molecules in hepatocytes. Our findings implicate unexpected Kupfferhepatocyte cross-talk in the control Plasmodium liver stage infection and demonstrate that TREM2 is involved in host responses against the malaria parasite. M alaria liver stage infection is asymptomatic but is absolutely required in the progression of Plasmodium infection in the vertebrate host, preceding propagation of parasites in the blood and clinical manifestations of malaria (1, 2). Current efforts in therapy and vaccine development include strategies aimed at deterring infection at the liver stage, preventing subsequent clinical complications and malaria transmission (3, 4). During liver stage infection, one Plasmodium sporozoite develops into thousands of merozoites inside each infected hepatocyte (5). Identification of host genetic factors that control liver parasite expansion may help elucidate response mechanisms operating during liver stage infection.Gene deficiency models and gene expression studies focusing on hepatocyte infection have highlighted genes that control hepatocyte invasion and intrahepatocyte parasite expansion [e.g., CD81 (6), SR-B1 (7, 8)], but the mechanisms of host response to liver stage infection remain elusive. It has been proposed that sporozoites' ability to traverse liver macrophages (9) and/or hepatocytes (10) in the course of liver stage infection may favor the release of proinflammatory factors at liver sites of sporozoite expansion (11,12). Innate immune mechanisms might be involved in sensing Plasmodium sporozoites and in controlling liver stage infection (13).Mouse models of liver stage infection suggest that sporozoites induce a innate in...

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 69%

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

Gonçalves

Rodrigues-Duarte

Rodo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…While TREM2 has been known primarily as a negative regulator of inflammatory response in macrophages, microglial cells, and dendritic cells (11)(12)(13)(14), a recent study (36) has reported that TREM2 amplifies the inflammatory response induced by Toll-like receptor in inflammatory bowel disease. However, whether TREM2 is involved in the inflammatory or anti-inflammatory response in adipose tissues has not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Promotes Adipogenesis and Diet-Induced Obesity

Park

Kim

et al. 2014

Diabetes

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Triggering receptor expressed on myeloid cells 2 (TREM2) is known to be involved in the anti-inflammatory response and osteoclast development. However, the role of TREM2 in adipogenesis or obesity has not yet been defined. The effect of TREM2 on adipogenesis and obesity was investigated in TREM2 transgenic (TG) mice on a high-fat diet (HFD). To block TREM2 signaling, a neutralizing fusion protein specific for TREM2 (TREM2-Ig) was used. TG mice were much more obese than wild-type mice after feeding with an HFD, independent of the quantity of food intake. These HFD-fed TG mice manifested adipocyte hypertrophy, glucose and insulin resistance, and hepatic steatosis. The expression of adipogenic regulator genes, such as peroxisome proliferator-activated receptor g and CCAAT/enhancerbinding protein a, was markedly increased in HFD-fed TG mice. Additionally, HFD-fed TG mice exhibited decreased Wnt10b expression and increased GSK-3b (glycogen synthase kinase-3b)-mediated b-catenin phosphorylation. In contrast, the blockade of TREM2 signaling using TREM2-Ig resulted in the inhibition of adipocyte differentiation in vitro and a reduction in body weight in vivo by downregulating the expression of adipogenic regulators. Our data demonstrate that TREM2 promotes adipogenesis and diet-induced obesity by upregulating adipogenic regulators in conjunction with inhibiting the Wnt10b/b-catenin signaling pathway.

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“…B6C3-Tg (APP/PS1⌬e9) 85Dbo/J mice (Jankowsky et al, 2001) as well as B6SJL-Tg(5XFAD) mice (Oakley et al, 2006) were obtained from The Jackson Laboratory. At 12 months of age, APP/PS1⌬e9 animals were treated with 100 mg/kg bexarotene (Targretin) or water by oral gavage for 5 d before slice phagocytosis, or 7 d (Cramer et al, 2012) before death. Targretin (75 mg) was dispersed in H 2 O to a concentration of 30 mg/ml, and animals received 100 l of solution by oral gavage, resulting in a treatment of 100 mg/kg/d.…”

Section: Methodsmentioning

confidence: 99%

“…RXR agonist treatment has been shown to improve behavior and decrease both soluble and fibrillar forms of A␤ in several mouse models of AD (Jiang et al, 2008;Cramer et al, 2012), although others have failed to observe these effects (Tesseur and De Strooper, 2013). We treated 12-month-old APP/PS1⌬e9 animals with bexarotene by oral gavage for 7 d. We found acute bexarotene treatment reduced the number of plaques in both cortex and hippocampus by 20% and 30%, respectively, as measured by the number of thioflavin S-positive plaques ( Fig.…”

Section: Rxr Activation Reduces Plaque Burden In 12 Month App/ps1⌬e9 mentioning

confidence: 99%

Nuclear Receptors License Phagocytosis by Trem2⁺Myeloid Cells in Mouse Models of Alzheimer's Disease

Savage¹,

Jay

Goduni³

et al. 2015

J. Neurosci.

136

120

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/Axlϩ macrophages revealed that they also expressed the phagocytic receptor TREM2 and high levels of CD45, consistent with a peripheral origin of these cells. Importantly, in an ex vivo slice assay, nuclear receptor agonist treatment reversed the AD-related suppression of phagocytosis through a MerTK-dependent mechanism. Thus, nuclear receptor agonists increase MerTK and Axl expression on plaque-associated immune cells, consequently licensing their phagocytic activity and promoting plaque clearance.

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Bacterial Sensor Triggering Receptor Expressed on Myeloid Cells-2 Regulates the Mucosal Inflammatory Response

Cited by 51 publications

References 32 publications

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Promotes Adipogenesis and Diet-Induced Obesity

Nuclear Receptors License Phagocytosis by Trem2⁺Myeloid Cells in Mouse Models of Alzheimer's Disease

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Bacterial Sensor Triggering Receptor Expressed on Myeloid Cells-2 Regulates the Mucosal Inflammatory Response

Cited by 51 publications

References 32 publications

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Promotes Adipogenesis and Diet-Induced Obesity

Nuclear Receptors License Phagocytosis by Trem2+Myeloid Cells in Mouse Models of Alzheimer's Disease

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Nuclear Receptors License Phagocytosis by Trem2⁺Myeloid Cells in Mouse Models of Alzheimer's Disease