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oai:repisalud.isciii.es:20.500.12105/270022025-12-18T12:57:32Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Galán, Miguel author Fernández-Méndez, Laura author Núñez, Vanessa author Femenía-Muiña, Marcos author Figuera-Belmonte, Pau author Moya-Ruiz, Elena author Martínez-Cano, Sarai author Hernández-García, Elena author Rodrigo-Tapias, Manuel author Rodríguez-Ronchel, Ana author Relaño-Rupérez, Carlos author Wculek, Stefanie K author Benguria, Alberto author Dopazo, Ana author Henri, Sandrine author Jo, Suin author Liu, Tian-Tian author Malissen, Bernard author Murphy, Kenneth M author Ramiro, Almudena R author Carregal-Romero, Susana author Ruiz-Cabello, Jesús author Robles-Vera, Iñaki author Sancho, David author 2025-07-18 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. We tested atherosclerosis in 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 and Δ32 mice, into lethally irradiated 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. Expansion of DCs in mice fed HCD for 8 weeks led to increased atherosclerotic lesion, which was prevented when mice were grafted before DC expansion with 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 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. 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. Circ Res. 2025 Jul 18;137(3):400-416. CIRCULATION RESEARCH 40444360 https://hdl.handle.net/20.500.12105/27002 atherosclerosis dendritic cells immunotherapy mice nanoparticles cDC1s Promote Atherosclerosis via Local Immunity and Are Targetable for Therapy.