Enhanced antigen presentation by macrophages promotes human atherosclerosis progression: therapeutic implications.

Abstract

Atherosclerosis is a chronic inflammatory disease of the arterial wall, where modified self-antigens cause sustained adaptive immune responses driven by clonal expansion of CD4+ effector T cells in situ. Although immune tolerance-inducing vaccination strategies show promise in animal models, their clinical translation is limited by the unclear role of adaptive immune responses in human atherosclerosis. RNA sequencing and immunohistochemistry were employed in human atherosclerotic plaques. Nuclear run-on, CRISPRi/a, RNA pull-down, ChIP-qPCR, and flow cytometry were utilized to investigate the lncRNA-dependent regulatory mechanism. Functional validation was performed in Apoe-/- mice through perivascular or intravenous siRNA delivery, as well as perivascular administration of macrophage-targeting lipid nanoparticles carrying dCas9-VP64 mRNA and the guide RNA. Major histocompatibility complex class II (MHCII)-dependent antigen presentation pathways were progressively activated in lesional macrophages as human atherosclerosis advanced. This activation was associated with increased CIITA expression, driven by enhanced transcription of its antisense-lncRNA (CIITA-AS1) and alternative splicing generating a non-coding transcript. Knockdown of these two lncRNAs reduced MHCII levels in human macrophages, thereby suppressing co-cultured T-cell activation. Mechanistically, CIITA-AS1 transcription promoted CIITA expression through STAT1 recruitment. Enforcing antisense-strand transcription of Ciita in lesional macrophages up-regulated Ciita and MHCII expression, exacerbating atherosclerosis in mice. Conversely, inhibition of macrophage antigen presentation via siRNA-mediated Ciita silencing attenuated atherosclerosis by reducing T-cell-mediated inflammation. This study reveals that CIITA-induced antigen presentation in macrophages activates local T-cell inflammatory response, promoting plaque progression. Targeting this pathway may improve vaccination efficacy by creating anti-inflammatory niches within plaques, offering a novel therapeutic strategy for atherosclerosis.