TREM-2 promotes Th1 responses by interacting with the CD3ζ-ZAP70 complex following Mycobacterium tuberculosis infection

Wu, Yongjian; Wu, Minhao; Ming, Siqi; Zhan, Xiaozhi; Hu, Shengfeng; Li, Xingyu; Yin, Huan; Cao, Can; Liu, Jiao; Li, Jinai; Wu, Zhi‐Yong; Zhou, Jie; Liu, Lei; Gong, Sitang; He, Duanman; Huang, Xi

doi:10.1172/jci137407

Cited by 21 publications

(15 citation statements)

References 56 publications

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“…Interestingly, we report that temporal deletion of Trem2 specifically on macrophages, using the CX3CR1 creER Trem2 flox Ldlr -/- model, does not recapitulate the systemic effects seen with whole body Trem2 -/- . This leads us to hypothesize that differences between models could be due either to developmental defects that require Trem2, such as in brain or liver, or another possibility is that Trem2 deletion influences cell function in non-macrophages subsets, as Trem2 expression is not restricted to only macrophages 63,64 . Despite differences seen between these models, our findings align with the aforementioned studies and support the idea that Trem2 is a master regulator of lipid associated macrophage (LAM) function and phenotype across disease subtypes.…”

Section: Discussionmentioning

confidence: 99%

Trem2 Promotes Foamy Macrophage Lipid Uptake and Survival in Atherosclerosis

Patterson

Firulyova

et al. 2022

Preprint

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Atherosclerotic plaque formation is driven by the continued expansion of cholesterol loaded foamy macrophages within the arterial intima. Foamy macrophages are primarily derived from newly recruited monocytes, but factors regulating monocyte specification toward foamy macrophage differentiation and prolonged survival in plaque remain poorly understood. We used trajectory analysis of integrated single cell RNA-seq data, along with a genome-wide CRISPR screening approach to identify Triggering Receptor Expressed on Myeloid Cells 2 (Trem2) as a candidate regulator for foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up additional oxidized low density lipoprotein (LDL) cholesterol in vitro. Competitive chimera experiments showed that Trem2-deficient macrophages were less competent to form foamy macrophages when competed against Trem2-sufficient macrophages in vivo. In addition, myeloid specific conditional deletion of Trem2 resulted in a dramatic attenuation of plaque progression, even when targeted in established atherosclerotic lesions. This was independent of changes in circulating inflammatory cytokines, monocyte recruitment, or serum cholesterol levels, but due to a reduction in plaque macrophage proliferation and enhanced cell death. Mechanistically, we link Trem2-deficient macrophages with an inability for cells to sense cholesterol loading and failure to upregulate efflux molecules. Accumulation of cholesterol in the endoplasmic reticulum enhanced activation of the ER-stress response that increased susceptibility for cholesterol-toxicity and cell death in foamy Trem2-deficient macrophages. Overall, this study identifies Trem2 as a regulator of foamy macrophage differentiation, atherosclerotic plaque growth, and as a putative therapeutic target for future intervention studies.

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Section: Discussionmentioning

confidence: 99%

Trem2 Promotes Foamy Macrophage Lipid Uptake and Survival in Atherosclerosis

Patterson

Firulyova

et al. 2022

Preprint

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“…By contrast, a recent study demonstrated that Trem2 upregulation on CD4 + T cells promoted Th1-mediated host defense against Mycobacterium tuberculosis infection in both mice and humans [54]. Conditional depletion of Trem2 in CD4 T cells as well as transfer of Trem2 de cient CD4 T cells into Rag −/− mice resulted in increased bacterial load and more severe lung pathology relative to Trem2 su cient counterparts [54]. These results imply that the metabolite and proin ammatory milieu at the site of initial T cell activation can in uence T cell activity via both Trem2 expressing myeloid cells or ligands engaging Trem2 on T cells.…”

Section: Discussionmentioning

confidence: 80%

“…The cerebrospinal uid from AD patients harbors clonally expanded CD8 T cells [52]; however, Trem2 de ciency in an AD mouse model did not alter CNS T cell numbers [53]. By contrast, a recent study demonstrated that Trem2 upregulation on CD4 + T cells promoted Th1-mediated host defense against Mycobacterium tuberculosis infection in both mice and humans [54]. Conditional depletion of Trem2 in CD4 T cells as well as transfer of Trem2 de cient CD4 T cells into Rag −/− mice resulted in increased bacterial load and more severe lung pathology relative to Trem2 su cient counterparts [54].…”

Section: Discussionmentioning

confidence: 98%

Trem2 deficiency impairs recovery and phagocytosis by dysregulating myeloid gene expression during virus induced demyelination

Hwang

Savarin

Kim

et al. 2022

Preprint

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Background Triggering receptor expressed on myeloid cells 2 (Trem2) plays a protective role in neurodegenerative diseases. By contrast, Trem2 functions can exacerbate tissue damage during respiratory viral or liver infections. We therefore investigated the role of Trem2 in a viral encephalomyelitis model associated with prominent Th1 mediated antiviral immunity leading to demyelination. Method Wild type (WT) and Trem2−/− mice were infected with a sublethal glia tropic murine coronavirus (MHV-JHM) intracranially. Disease progression and survival were monitored daily. leukocyte accumulation and pathological features including demyelination and axonal damage in spinal cords (SC) were determined by flow cytometry and tissue section immunofluorescence analysis. Expression of select inflammatory cytokines and chemokines was measured by RT-PCR and global myeloid cell gene expression in SC-derived microglia and infiltrated bone marrow-derived macrophages (BMDM) were determined using the Nanostring nCounter platform. Results BMDM recruited to SCs in response to infection highly upregulated Trem2 mRNA compared to microglia coincident with viral control. Trem2 deficiency did not alter disease onset or severity, but impaired clinical recovery after onset of demyelination. Disease progression in Trem2−/− mice could not be attributed to altered virus control or a dysregulated inflammatory response. A prominent difference was increased degenerated myelin not associated with the myeloid cell markers IBA1 and/or CD68. Gene expression profiles of SC-derived microglia and BMDM further revealed that Trem2 deficiency resulted in impaired upregulation of phagocytosis associated genes Lpl and Cd36 in microglia, but a more complex pattern in BMDM. Conclusions Trem2 deficiency during viral induced demyelination dysregulates expression of other select genes regulating phagocytic pathways and lipid metabolism, with distinct effects on microglia and BMDM. The ultimate failure to remove damaged myelin is reminiscent of other demyelination models and supports that Trem2 function is mainly regulated by sensing a dysregulated lipid environment, independent of the initial insult or the inflammatory milieu.

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“…In fact, the expression level of ZAP70 was higher in AD hippocampus ( 84 ). Also, AD risk factors apolipoprotein E and TREM2 can activate ZAP70 to trigger downstream signaling pathways ( 85 , 86 ). These observations indicate that ZAP70 is a potentially critical kinase in AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%