巨噬细胞亚群中SEMA4A信号传导及其在骨关节炎中的意义

摘要(中文译文)

骨关节炎（OA）是一种常见的退行性疾病，以关节软骨退变为特征，全球约影响2.4亿人。低度炎症——尤其是巨噬细胞极化失衡——是骨关节炎进展的关键因素。M1型巨噬细胞通过分泌促炎因子和基质降解酶加剧软骨破坏，而M2型巨噬细胞则通过抗炎因子促进修复。尽管已有研究报道了OA中巨噬细胞极化的变化，但巨噬细胞亚群通讯架构及动态状态转换过程中的主导配体-受体轴仍不清楚——这正是本整合框架旨在解决的问题。本研究利用单细胞转录组数据，包括6例正常样本和12例OA样本，系统分析OA进展过程中M1/M2巨噬细胞的相互作用模式及关键配体-受体对。方法包括细胞亚群注释、GSVA功能富集、拟时序轨迹分析和hdWGCNA网络构建。本研究为OA的炎症机制提供了单细胞水平的证据。细胞间通讯分析揭示了M1与M2巨噬细胞之间强烈的双向相互作用。巨噬细胞亚群、拟时序、hdWGCNA及细胞间通讯分析的整合分析确定SEMA4A为唯一重叠的关键基因。SEMA4信号通路在巨噬细胞亚群间表现出活跃的通讯，其中M1巨噬细胞作为主导信号发送者。配体-受体分析显示SEMA4A-PLXNB2是通讯概率最高的主要相互作用对。本研究发现了SEMA4A沿巨噬细胞拟时序轨迹呈现动态的“先增后减”表达模式，提示其参与巨噬细胞分化和状态转换。配体-受体分析揭示SEMA4A-PLXNB2是巨噬细胞亚群间的主导相互作用信号通路，M1巨噬细胞在信号发送和接收中充当中心枢纽。结合既往证据表明SEMA4A与NF-κB形成正反馈环路并放大IL-6/TNF-α的产生，从而促进软骨分解代谢和组织重塑，这些发现表明，在骨关节炎关节中，SEMA4A-PLXNB2信号通路通过巨噬细胞-基质细胞串扰维持并放大炎症微环境，是一个有待进一步验证的潜在治疗候选靶点。SEMA4A-PLXNB2信号通路在巨噬细胞相关炎症网络中发挥重要作用，可能促进OA进展，是一个有待进一步验证的潜在治疗候选靶点。

Abstract

Osteoarthritis (OA) is a common degenerative disease characterized by the deterioration of articular cartilage, affecting approximately 240 million people worldwide. Low-grade inflammation-particularly the imbalance in macrophage polarization-is a critical factor in osteoarthritis progression. M1-type macrophages exacerbate cartilage destruction by secreting pro-inflammatory factors and matrix-degrading enzymes, while M2-type macrophages promote repair through anti-inflammatory factors. While macrophage polarization changes in OA have been reported, the macrophage subpopulation communication architecture and dominant ligand-receptor axes across dynamic state transitions remain unclear-and that this is what our integrated framework aims to address. This study leverages single-cell transcriptomic data, including 6 normal samples and 12 OA samples, to systematically analyze the interaction patterns and key ligand-receptor pairs of M1/M2 macrophages during OA progression. Methods include cell subset annotation, GSVA functional enrichment, pseudotemporal trajectory analysis, and hdWGCNA network construction. This study provides single-cell-level evidence for the inflammatory mechanisms of OA. Cell-cell communication analysis revealed strong bidirectional interactions between M1 and M2 macrophages. Integrative analysis of macrophage subpopulations, pseudotime, hdWGCNA, and cell-cell communication analysis identified SEMA4A as the only overlapping key gene. The SEMA4 signaling pathway exhibited active communication among macrophage subpopulations, with M1 macrophages acting as dominant signal senders. Ligand-receptor analysis showed that SEMA4A-PLXNB2 was the predominant interaction pair with the highest communication probability. This study identified a dynamic "increase-then-decrease" expression pattern of SEMA4A along the macrophage pseudotime trajectory, suggesting its involvement in macrophage differentiation and state transitions. Ligand-receptor analysis revealed SEMA4A-PLXNB2 as the dominant interaction signaling pathway among macrophage subpopulations, with M1 macrophages acting as central hubs in sending and receiving signals. Together with previous evidence that SEMA4A forms a positive feedback loop with NF-κB and amplifies IL-6/TNF-α production, thereby promoting cartilage catabolism and tissue remodeling, these findings indicate that, in osteoarthritic joints, SEMA4A-PLXNB2 signaling pathway sustains and amplifies the inflammatory microenvironment through macrophage-stromal crosstalk and represents a potential therapeutic candidate that warrants further validation. The SEMA4A-PLXNB2 signaling pathway plays an important role in the macrophage-associated inflammatory network and may contribute to the progression of OA, representing a potential therapeutic candidate warranting further validation.

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