{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:28:14Z","timestamp":1787243294972,"version":"build-2736575974"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Osteoarthritis (OA) is a common degenerative disease characterized by the deterioration of articular cartilage, affecting approximately 240 million people worldwide. Low-grade inflammation\u2014particularly the imbalance in macrophage polarization\u2014is 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\u2013receptor axes across dynamic state transitions remain unclear\u2014and that this is what our integrated framework aims to address.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u2013receptor analysis showed that SEMA4A\u2013PLXNB2 was the predominant interaction pair with the highest communication probability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study identified a dynamic \u201cincrease-then-decrease\u201d expression pattern of SEMA4A along the macrophage pseudotime trajectory, suggesting its involvement in macrophage differentiation and state transitions. Ligand\u2013receptor analysis revealed SEMA4A\u2013PLXNB2 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-\u03baB and amplifies IL-6\/TNF-\u03b1 production, thereby promoting cartilage catabolism and tissue remodeling, these findings indicate that, in osteoarthritic joints, SEMA4A\u2013PLXNB2 signaling pathway sustains and amplifies the inflammatory microenvironment through macrophage\u2013stromal crosstalk and represents a potential therapeutic candidate that warrants further validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The SEMA4A\u2013PLXNB2 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.<\/jats:p>\n                  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