{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:50:57Z","timestamp":1782449457705,"version":"3.54.5"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"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:p>\n                    Xylosyltransferase-II (XT-II), encoded by\n                    <jats:italic>XYLT2<\/jats:italic>\n                    , catalyzes the rate-limiting initial step of proteoglycan biosynthesis. Pathogenic mutations in\n                    <jats:italic>XYLT2<\/jats:italic>\n                    cause spondylo-ocular syndrome (SOS), a rare disorder characterized by severe primary osteoporosis, skeletal dysplasia, and additional systemic manifestations. Although dysregulated macrophage polarization has been linked to bone remodeling disorders such as osteoporosis, which are associated with an imbalance toward pro-inflammatory and osteoclastogenic signaling, the role of XT-II in macrophage biology remains unexplored. In the present study, siRNA-mediated knockdown of\n                    <jats:italic>XYLT2<\/jats:italic>\n                    was performed in human primary macrophages across three polarization states (M0, M1, M2) to investigate the impact of XT-II deficiency on macrophage polarization and inflammatory signaling. At the phenotypic level,\n                    <jats:italic>XYLT2<\/jats:italic>\n                    deficiency destabilized M2 macrophage identity, as shown by significant reductions in M2-associated marker expression, including interleukin 1\u03b2, interleukin 6, CD163, and CD206, and impaired phagocytic capacity. A paradoxical reduction of pro-inflammatory markers alongside the induction of M2-associated features was observed in M1 macrophages, indicating a broader disruption of polarization boundary maintenance. The\n                    <jats:italic>XYLT2<\/jats:italic>\n                    deficiency also promoted pro-inflammatory activation in unpolarized M0 macrophages. Cytokine profiling revealed a predominantly pro-inflammatory secretory shift, with exceptional induction of CXCL10 across all polarization states. At the signaling level,\n                    <jats:italic>XYLT2<\/jats:italic>\n                    knockdown resulted in a reciprocal shift, characterized by suppression of NF-\u03baB pathway components and nuclear p65 translocation alongside the constitutive activation of STAT1 and STAT3. Transcriptome-wide profiling by bulk mRNA sequencing confirmed a conserved interferon-associated gene expression program across all polarization states, with significant enrichment of innate immune sensing, JAK-STAT, and cytokine signaling pathways among upregulated genes. In summary, these findings demonstrate that XT-II fulfills an important role in maintaining macrophage polarization and that its deficiency induces a reprogramming of pro-inflammatory signaling, extracellular matrix remodeling, and cellular interactions in bone-relevant cell types. This is associated with transcriptional changes linked to osteoclast differentiation and altered bone-associated immune signaling, suggesting that\n                    <jats:italic>XYLT2<\/jats:italic>\n                    deficiency may contribute to impaired bone homeostasis and providing new insights into the pathomechanisms of SOS.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1850248","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:34:26Z","timestamp":1782448466000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Xylosyltransferase-II deficiency rewires innate immune signaling and destabilizes polarization in human macrophages"],"prefix":"10.3389","volume":"17","author":[{"given":"Alina","family":"Witt","sequence":"first","affiliation":[{"name":"Herz- und Diabeteszentrum Nordrhein-Westfalen, Institut f\u00fcr Laboratoriums- und Transfusionsmedizin, 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