Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling.
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.
Background Vision is a crucial sense for the evolutionary success of many animal groups. Here we explore the diversity of visual pigments (opsins) in the transcriptomes of amphipods (Crustacea: Amphipoda) and conclude that it is restricted to middle (MWS) and long wavelength-sensitive (LWS) opsins in the overwhelming majority of examined species. Results We evidenced (i) parallel loss of MWS opsin expression in multiple species (including two independently evolved lineages from the deep and ancient Lake Baikal) and (ii) LWS opsin amplification (up to five transcripts) in both Baikal lineages. The number of LWS opsins negatively correlated with habitat depth in Baikal amphipods. Some LWS opsins in Baikal amphipods contained MWS-like substitutions, suggesting that they might have undergone spectral tuning. Conclusions This repeating two-step evolutionary scenario suggests common triggers, possibly the lack of light during the periods when Baikal was permanently covered with thick ice and its subsequent melting. Overall, this observation demonstrates the possibility of revealing climate history by following the evolutionary changes in protein families.
Rheumatic heart disease (RHD) is a major cause of valvular heart disease in developing nations. Endothelial cells (ECs) are considered crucial contributors to RHD, but greater insight into contributing mechanisms is needed. Cdh5-driven EC lineage tracing in the K/B.g7 mouse model of autoimmune valvular carditis revealed new capillary lymphatic vessels that develop from valve surface endothelial cells during the progression of disease. Human rheumatic valves contained similar lymphatics. Unsupervised clustering of mitral valve single-cell RNA sequencing data revealed lymphatic valve ECs (VECs) that express a transcriptional profile distinct from other VEC populations and upregulate genes controlling extracellular matrix composition and fibrosis during disease progression. Finally, inhibiting VEGFR3 prevented expansion of this mitral valve lymphatic network and decreased valve thickening and collagen density. These studies reveal a novel form of postnatal pathogenic lymphangiogenesis that promotes autoimmune valvular carditis.
Pancreatic ductal adenocarcinoma (PDA) is a lethal and metastatic malignancy resistant to therapy. Elucidating how pancreatic tumor-specific T cells differentiate and are maintained in vivo could inform novel therapeutic avenues to promote T cell antitumor activity. Here, we show that the spleen is a critical site harboring tumor-specific CD8 T cells that functionally segregate based on differential Cxcr3 and Klrg1 expression. Cxcr3+ Klrg1- T cells express the memory stem cell marker Tcf1, whereas Cxcr3-Klrg1 + T cells express GzmB consistent with terminal differentiation. We identify a Cxcr3+ Klrg1+ intermediate T cell subpopulation in the spleen that is highly enriched for tumor specificity. However, tumor-specific T cells infiltrating primary tumors progressively downregulate both Cxcr3 and Klrg1 while upregulating exhaustion markers PD-1 and Lag-3. We show that antigen-specific T cell infiltration into PDA is Cxcr3 independent. Further, Cxcr3-deficiency results in enhanced antigen-specific T cell IFNγ production in primary tumors, suggesting that Cxcr3 promotes loss of effector function. Ultimately, however, Cxcr3 was critical for mitigating cancer cell dissemination following immunotherapy with CD40 agonist + anti-PD-L1 or T cell receptor engineered T cell therapy targeting mesothelin. In the absence of Cxcr3, splenic Klrg1 + GzmB + antitumor T cells wain while pancreatic cancer disseminates suggesting a role for these cells in eliminating circulating metastatic tumor cells. Intratumoral myeloid cells are poised to produce Cxcl10, whereas splenic DC subsets produce Cxcl9 following immunotherapy supporting differential roles for these chemokines on T cell differentiation. Together, our study supports that Cxcr3 mitigates tumor cell dissemination by impacting peripheral T cell fate rather than intratumoral T cell trafficking.
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