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Junctional Adhesion Molecule-A is dispensable for myeloid cell recruitment and diversification in the tumor microenvironment

ABSTRACT: Junctional Adhesion Molecule-A (JAM-A), expressed on the surface of myeloid cells, is required for extravasation at sites of inflammation and may also modulate macrophage activation. Myeloid cell infiltration is a common feature of tumors that drives disease progression, but the function of JAM-A in this phenomenon and its impact on cancer-associated myeloid cells is little understood. Here we show that systemic cancer-induced inflammation in mice enhanced JAM-A expression in an IL1β-dependent manner specifically on circulating monocytes. However, using myeloid-specific JAM-A-deficient mice, we found that JAM-A was dispensable for recruitment of monocytes and other myeloid cells to tumors, in contrast to its reported role in inflammation. Single-cell RNA sequencing revealed that the loss of JAM-A did not influence the transcriptional reprogramming of tumor-infiltrating myeloid cells. Overall, our results support the notion that cancer-associated inflammation can modulate the phenotype of circulating immune cells and we demonstrate that tumors can bypass the requirement of JAM-A for myeloid cell recruitment.

ORGANISM(S): Mus musculus

PROVIDER: GSE210226 | GEO | 2022/08/04

REPOSITORIES: GEO

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Project description:Background: Monocytes and macrophages are implicated in inflammation and atherosclerosis, whereas monocytes are involved in psoriasis lesion formation. We previously reported a psoriatic inflammation-associated significant decrease in the membrane protein caveolin-1 (CAV-1) in psoriasis patient monocytes. However, the phenotype of circulating monocytes and their macrophage differentiation in psoriasis patients remain unclear. Objective: We sought to clarify circulating monocyte and monocyte-derived macrophage (MDM) phenotypes in psoriasis patients with and without comorbidities. Method: Thirty-one patients with psoriasis vulgaris and 28 control subjects were included. Surface macrophage markers and inflammatory status were examined in circulating monocytes and MDMs from both groups. Expression of CD36, which mediates macrophage uptake of oxidized low-density lipoprotein (oxLDL), was evaluated in these cells. CAV-1-silenced monocytes were differentiated into macrophages to investigate the effects of CAV-1 downregulation on psoriatic inflammation and atherosclerosis. Results: Macrophage surface markers were detectable in circulating monocytes. A significant M1 shift was detected in monocytes and MDMs in psoriasis patients, including those without cardiovascular disease risk factors, as compared to controls. MDMs of psoriasis patients had more CD36-expressing cells, which are associated with atherosclerosis risk. Additionally, CAV-1-silencing in monocytes increased the likelihood of M1-biased macrophage differentiation and increased pro-inflammatory cytokine production. Conclusions: Monocytes from psoriasis patients were more likely to differentiate into M1-dominant macrophages, correlating with inflammatory status and CAV-1 expression. These aberrant inflammatory monocytes not only contribute to psoriatic inflammation by producing psoriatic cytokines, but also have a phenotype that could increase atherosclerosis risk by uptake of oxLDL and formation of foam cells.

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Junctional Adhesion Molecule-A is dispensable for myeloid cell recruitment and diversification in the tumor microenvironment

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