cDC1s Promote Atherosclerosis via Local Immunity and Are Targetable for Therapy
Year: 2025
Type: article
Abstract: BACKGROUND: Atherosclerosis is characterized by immune cell accumulation in the arterial wall and adaptive CD4 + T helper 1 immunity contributes to atherosclerosis development. However, how conventional dendritic cells (DCs) orchestrate this adaptive response remains controversial. This study unveils strategies for the gain and loss of function of cDCs to decipher their role in atherosclerosis induction in relation to adaptive T-cell immunity. METHODS: We tested atherosclerosis in Ldlr −/− mice fed a high-cholesterol diet (HCD). Expansion of DCs in vivo was achieved by overexpression of FLT3L (Fms-like tyrosine kinase 3 ligand), while the effect of ablation of conventional type 1 DCs (cDC1s) in atherosclerosis was analyzed by grafting bone marrow from different mouse models of cDC1 depletion, including Xcr1 Cre−DTA and Irf8 Δ32 mice, into lethally irradiated Ldlr −/− recipients before HCD. CD3 + T-cell subsets were analyzed using flow cytometry or single-cell RNA sequencing (scRNA-seq). Nanoparticles loaded with dexamethasone and decorated with anti-CLEC9A antibody to target cDC1s were tested for immunotherapy. RESULTS: Expansion of DCs in Ldlr − / − mice fed HCD for 8 weeks led to increased atherosclerotic lesion, which was prevented when Ldlr − / − mice were grafted before DC expansion with Xcr1 Cre−DTA cDC1-depleted bone marrow compared with controls. Consistently, even in the absence of DC expansion, cDC1 deficiency prevented HCD-induced atherosclerosis. The scRNA-seq analysis of aortic CD3 + T cells in this experimental approach showed a local reduction in CD4 + Th1 and CD8 + IFN (interferon)-γ + T cells in the absence of cDC1s compared with control mice. Mechanistically, stimulator of IFN genes (STING) in cDC1s was required for the proatherogenic function of cDC1s. As a potential cDC1-targeted immunotherapy for atherosclerosis, we generated lipid nanoparticles decorated with an anti-CLEC9A antibody to specifically target cDC1s. When loaded with the immunosuppressive drug dexamethasone, these nanoparticles promoted a reduction of the atherosclerotic lesion in Ldlr − / − mice fed HCD, correlating with decreased CD4 + Th1 and CD8 + IFN-γ + T cells in the spleen. These immunosuppressive nanoparticles, however, did not impair antiviral response. CONCLUSIONS: Using state-of-the-art strategies, our results establish that cDC1s have a proatherogenic role in atherosclerosis by boosting CD4 + and CD8 + T-cell immunity and propose that cDC1s can be targeted with an immunosuppressive drug to decrease atherosclerosis progression.
Source: Circulation Research
Authors: Miguel Galán, Laura Fernández-Méndez, Vanessa Núñez, Marcos Femenía-Muiña, Pau Figuera-Belmonte, Elena Moya-Ruiz, Sarai Martínez-Cano, Elena Hernández-García, Manuel Rodrigo-Tapias, Ana Rodríguez-Ronchel, Carlos Relaño-Rupérez, Stefanie K. Wculek, Alberto Benguria, Ana Dopazo, Sandrine Henri, Suin Jo, Tian-Tian Liu, Bernard Malissen, Kenneth M. Murphy, Almudena R. Ramiro, Susana Carregal-Romero, Jesús Ruiz-Cabello, Iñaki Robles-Vera, David Sancho
Institutions: Spanish National Centre for Cardiovascular Research, Universidad Autónoma de Madrid, University of the Basque Country, CIC biomaGUNE, Universidad Complutense de Madrid, Inmunotek (Spain), Institute for Research in Biomedicine, Barcelona Institute of Science and Technology, Centro de Investigación en Red en Enfermedades Cardiovasculares, Centro de Investigación Biomédica en Red, Université de Tours, Centre National de la Recherche Scientifique, Inserm, Aix-Marseille Université, Centre d’Immunologie de Marseille-Luminy, Centre d'Étude des Pathologies Respiratoires, Washington University in St. Louis, Ikerbasque, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4410901383