Vassallo, S. | Search bioRxiv

bioRxiv2025

CD300e Controls Macrophage Lipid Handling and Safeguards Adipose Tissue Function in Obesity

Previous studies in monozygotic twins discordant for body mass index (BMI) revealed that obese individuals exhibit elevated expression of the immune receptor CD300e in white adipose tissue (WAT). Notably, CD300e levels decreased following weight loss, implicating its involvement in adipose tissue remodeling and metabolic regulation. To elucidate the functional role of CD300e, we employed a Cd300e knockout (Cd300e-/-) mouse model subjected to a high-fat diet (HFD). Our findings demonstrate that CD300e deficiency exacerbates obesity-associated metabolic dysfunction, including increased weight gain, adipocyte hypertrophy, hepatic steatosis, and impaired glucose and insulin sensitivity. Adipose tissue macrophages (ATMs) lacking CD300e displayed reduced lipid and glucose uptake, alongside diminished mitochondrial respiration--a phenotype consistent with a broader metabolic impairment, as evidenced by proteomic profiling. These metabolic deficits were genotype-dependent and persisted after 16 weeks of HFD. Concurrently, adipocytes from Cd300e-/- mice exhibited enhanced lipogenesis and attenuated lipolysis. Remarkably, the impaired metabolic fitness exhibited by Cd300e-/- mouse macrophages was recapitulated in human cells upon gene silencing. Collectively, these results establish CD300e as essential for ATM metabolic activation, positioning it as a key regulator of adipose tissue homeostasis and a critical mediator of obesity-induced metabolic dysfunction. Given its pivotal role, CD300e emerges as a promising therapeutic target for modulating adipose tissue function and improving metabolic health in obesity.

immunology↗

bioRxiv2024

CD300e as a Driver of Immunosuppressive Tumor Microenvironment in Colorectal Cancer

Colorectal cancer (CRC) progression is shaped by the tumor microenvironment, particularly tumor-associated macrophages (TAMs), which often adopt immunosuppressive functions. CD300e, a myeloid receptor involved in immune regulation, has an uncharacterized role in CRC. Here, we show that CD300e is selectively upregulated in tumor-infiltrating monocytes and macrophages, driving a suppressive phenotype marked by impaired antigen presentation. In vitro cocultures of patient-derived tumor organoids and human monocytes revealed that tumor-derived signals induce CD300e expression and promote a protumorigenic macrophage profile. Using CD300e knockout mice in AOM/DSS and MC38 CRC models, we found that CD300e loss reduced tumor burden, enhanced MHC expression on TAMs, and improved T-cell responses. Transcriptomic and functional analyses demonstrated that CD300e-deficient macrophages exhibit increased phagocytosis, upregulated antigen presentation, and greater support for T-cell proliferation and cytotoxicity. Adoptive transfer confirmed that macrophage-intrinsic CD300e expression is sufficient to suppress T-cell function and promote tumor growth. Our findings identify CD300e as a critical regulator of macrophage-mediated immune suppression in CRC and a potential target for reprogramming TAMs to enhance immunotherapy.

cancer biology↗