TREM-2 Promotes Host Resistance AgainstPseudomonas aeruginosaInfection by Suppressing Corneal Inflammation via a PI3K/Akt Signaling Pathway

Sun, Mingxia; Zhu, Min; Chen, Kang; Nie, Xinxin; Deng, Qiuchan; Hazlett, Linda D.; Wu, Yongjian; Li, Meiyu; Wu, Minhao; Huang, Xi

doi:10.1167/iovs.12-10938

Cited by 58 publications

(56 citation statements)

References 56 publications

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“…2-4), suggesting that DAP12 mediated the miR-183/96/182 function to promote proinflammatory cytokine production. This is consistent with the observation that TREM-2 also limits the production of proinflammatory cytokines in Mϕ and promotes host resistance against PA keratitis [39], similar to what we observed in miR-183/96/182 ko mice [13], suggesting that the DAP12-TREM-2 pathway contributes to miR-183/96/182 modulation on the proinflammatory responses of Mϕ and overall corneal responses to PA infection.…”

Section: Discussionsupporting

confidence: 92%

The miR-183/96/182 Cluster Regulates Macrophage Functions in Response to Pseudomonas aeruginosa

et al. 2019

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Macrophages (Mϕ) are an important component of the innate immune system; they play critical roles in the first line of defense to pathogen invasion and modulate adaptive immunity. MicroRNAs (miRNAs) are a newly recognized, important level of gene expression regulation. However, their roles in the regulation of Mϕ and the immune system are still not fully understood. In this report, we provide evidence that the conserved miR-183/96/182 cluster (miR-183/96/182) modulates Mϕ function in their production of reactive nitrogen (RNS) and oxygen species (ROS) and their inflammatory response to Pseudomonas aeruginosa (PA) infection and/or lipopolysaccharide (LPS) treatment. We show that knockdown of miR-183/96/182 results in decreased production of multiple proinflammatory cytokines in response to PA or LPS treatment in Mϕ-like Raw264.7 cells. Consistently, peritoneal Mϕ from miR-183/96/182-knockout versus wild-type mice are less responsive to PA or LPS, although their basal levels of proinflammatory cytokines are increased. In addition, overexpression of miR-183/96/182 results in decreased production of nitrite and ROS in Raw264.7 cells. We also provide evidence that DAP12 and Nox2 are downstream target genes of miR-183/96/182. These data suggest that miR-183/96/182 imposes global regulation on various aspects of Mϕ function through different downstream target genes.

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Section: Discussionsupporting

confidence: 92%

The miR-183/96/182 Cluster Regulates Macrophage Functions in Response to Pseudomonas aeruginosa

et al. 2019

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“…Expression of TREM2 in liver macrophages is in line with reports of its expression in resident macrophages in other tissues (21). TREM2 signaling was initially associated with negative regulation of macrophage activation (26), but multiple independent observations of TREM2 proinflammatory effects on macrophage activation in bacterial infections have been reported (27,28). This suggests that cellular functions of TREM2 may be context-dependent.…”

Section: Discussionsupporting

confidence: 81%

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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“…207 Factors that improve corneal inflammation include the apoptotic Fas pathway which regulates the production of proinflammatory cytokines 208 and a phospho-inositol-3-kinase (PI3K)/Akt pathway that activates a receptor known as triggering receptor expressed on myeloid cells 2 (TREM-2). 209 All of these reduce inflammation and tissue damage and may be avenues to explore further.…”

Section: Potential Targeted Molecular Therapiesmentioning

confidence: 99%

Pattern recognition receptors in microbial keratitis

Taube

Cendra

Elsahn

et al. 2015

Eye

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TREM-2 Promotes Host Resistance AgainstPseudomonas aeruginosaInfection by Suppressing Corneal Inflammation via a PI3K/Akt Signaling Pathway

Cited by 58 publications

References 56 publications

The miR-183/96/182 Cluster Regulates Macrophage Functions in Response to <b><i>Pseudomonas aeruginosa</i></b>

The miR-183/96/182 Cluster Regulates Macrophage Functions in Response to <b><i>Pseudomonas aeruginosa</i></b>

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

Pattern recognition receptors in microbial keratitis

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