{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:31:38Z","timestamp":1792096298761,"version":"4.4.0"},"reference-count":43,"publisher":"Begell House","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Crit Rev Immunol"],"published-print":{"date-parts":[[2026]]},"abstract":"<p>&lt;b&gt;Objectives: &lt;\/b&gt;Primary Sj\u00f6gren's syndrome (pSS) is characterized by molecular heterogeneity and immune-metabolic dysregulation. This study aimed to identify diagnostic biomarkers and characterize monocyte-macrophage differentiation trajectories in pSS.\n\n&lt;b&gt;Methods:&lt;\/b&gt; Bulk RNA-seq data were first batch-corrected and subjected to differential expression analysis, immune infiltration profiling, and weighted gene co-expression network analysis (WGCNA) to identify key gene modules. For single-cell RNA-seq, 42,157 salivary gland cells were clustered and annotated; Monocle3 pseudotime analysis reconstructed the monocyte-macrophage differentiation trajectory, and CellChat quantified intercellular signaling networks. Candidate immune-metabolism biomarkers were then screened by integrating WGCNA results with three machine-learning algorithms, LASSO regression, SVM-RFE, and random forest, and validated in the external GSE84844 cohort. Finally, functional relevance was tested in PMA-induced THP-1 macrophages by knocking down ISG15 and measuring effects on NF-&amp;kappa;B activation and secretion of TNF-&amp;alpha; and IL-1&amp;beta;.\n\n&lt;b&gt;Results: &lt;\/b&gt;Pseudotime analysis delineated a monocyte-to-macrophage differentiation axis and pinpointed 182 dynamic marker genes. Integrated machine-learning and network analysis highlighted four immune-metabolism genes&amp;#151;ISG15, OAS1, LAP3, and PARP9&amp;#151;each achieving AUC &gt; 0.80 in the GSE84844 validation set. &lt;i&gt;In vitro&lt;\/i&gt;, ISG15 knockdown markedly attenuated NF-&amp;kappa;B activation and reduced TNF-&amp;alpha;\/IL-1&amp;beta; release, confirming its pivotal role in pSS-associated inflammation.\n\n&lt;b&gt;Conclusions: &lt;\/b&gt;This integrated transcriptomic analysis highlights key monocyte-macrophage trajectories and identifies four robust immune\u2013metabolism biomarker candidates for pSS diagnosis. Functional validation of ISG15 suggests it plays a pivotal role in driving macrophage-mediated inflammatory responses in pSS.<\/p>","DOI":"10.1615\/critrevimmunol.2025060877","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T18:55:31Z","timestamp":1761072931000},"page":"1-16","source":"Crossref","is-referenced-by-count":1,"title":["Single-Cell Transcriptomic Analysis Reveals ISG15 as a Key Regulator of Macrophage-Mediated Inflammation Driving Primary Sj\u00f6gren's Syndrome Progression"],"prefix":"10.1615","volume":"46","author":[{"given":"Yajing","family":"Chao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalu","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"613","reference":[{"key":"2","unstructured":"Brito-Zer\u00f3n P, Retamozo S, Ramos-Casals M. 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