Jianguang Wang

Sepsis-induced acute lung injury (ALI) is a life-threatening condition associated with high mortality rates. While emerging evidence suggests that KIAA1199 (also known as cell migration-inducing protein, CEMIP) contributes to the pathogenesis of bacterial infections, its specific role in sepsis-induced ALI remains largely unexplored. In this study, we find that serum levels of KIAA1199 are significantly elevated in sepsis patients compared to healthy individuals, demonstrating a positive correlation with the SOFA scores. Additionally, we observe the expression of KIAA1199 increased in the lung tissue of septic mice, particularly in alveolar epithelial Type II (AT2) cells. We further generate AT2-specific KIAA1199 knockout mice on a male C57BL/6 J background and establish LPS-induced ALI model. The results indicate that KIAA1199-deficient mice exhibit improved survival rates, reduced lung injury, and decreased levels of proinflammatory cytokines. Transcriptomic analysis and functional validation reveal that KIAA1199 promotes pulmonary complement activation by downregulating complement factor H (CFH), a critical regulator of the alternative complement pathway. Mechanistically, KIAA1199 downregulates CFH expression by enhancing the ubiquitinated degradation of its transcription factor of p53. In conclusion, our data demonstrate that KIAA1199 exacerbates sepsis-induced ALI via promoting local complement activation through CFH suppression, which may serve as a potential therapeutic target for sepsis-induced ALI. The alternative text for this image may have been generated using AI.

The lymphatic system plays a central role in fluid transport and immune regulation, yet its contribution to sepsis remains incompletely understood. Analysis of more than 500,000 individuals from the UK Biobank reveals that lymphatic system disorders and genetic variants in FLT4 (VEGFR3) are strongly associated with increased sepsis risk. Single-cell RNA sequencing further shows a marked reduction of VEGFR3^high lymphatic endothelial cells during sepsis. LEC-specific deletion of VEGFR3 impairs lymphatic reflux without disrupting vessel architecture, leading to barrier failure, systemic inflammation, bacterial dissemination, and sepsis. Mechanistically, VEGFR3 sustains lymphatic glycocalyx integrity by promoting SOX18-dependent HSPG2 transcription and heparan sulfate biosynthesis. Consistently, LEC-specific HSPG2 knockdown or pharmacological inhibition of SOX18 phenocopies VEGFR3 deficiency, whereas heparan sulfate supplementation alleviates sepsis-like pathology. Moreover, HSPG2 genetic variants are significantly associated with both lymphatic disorders and sepsis. Collectively, these findings identify lymphatic reflux dysfunction as a pathogenic determinant of sepsis and establish disruption of the VEGFR3–SOX18–HSPG2–heparan sulfate axis as an active driver of disease.

Elevated lactate in the joint microenvironment of rheumatoid arthritis patients is crucial for disease progression, though the mechanism remains unclear. This study shows significantly increased global lactylation levels within fibroblast-like synoviocytes from RA patients compared to healthy controls, with lactylated proteins being enriched in histones. Furthermore, we find anti-lactylated histone autoantibodies present in RA patients that positively correlate with Disease Activity Score 28. Using CUT&Tag and RNA-seq, we identify NFATc2 as a key target gene regulated by histone H3 lysine 9 lactylation. Functional studies reveal that NFATc2 promotes migration of RA-FLSs. Additionally, using collagen antibody-induced arthritis and collagen-induced arthritis mouse models, we demonstrate that NFATc2 exacerbates RA disease progression through enhancing the cartilage invasive function of FLS. Here, we show that upregulated target gene NFATc2 by lactate-dependent histone lactylation, can be used as a potential therapeutic target for intervention, anti-lactylated histone autoantibodies is promising as a diagnostic marker for RA.

Protein citrullination modification plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA), and anti-citrullinated protein antibodies (ACPAs) are extensively employed for clinical diagnosis of RA. However, there remains limited understanding regarding specific citrullinated proteins and their implications in the progression of RA. In this study, we screen and verify insulin-like growth factor-2 mRNA binding protein 1 (IGF2BP1) as a novel citrullinated protein with significantly elevated citrullinated level in RA. Autoantibodies against citrullinated IGF2BP1 are further detected in serum and synovial fluid samples from RA patients, which are positively correlated with erythrocyte sedimentation rate (ESR) and disease activity score 28 (DAS28). Transcriptomic sequencing and functional verification show that citrullination at the R167 site of IGF2BP1 promotes the proliferation, migration, and invasion of RA fibroblast-like synoviocytes (RA-FLSs) by improving the mRNA stability of Semaphorin 3D (SEMA3D). Experiments in collagen-induced arthritis (CIA) mice, the classical animal model of RA, show that IGF2BP1 R176K point mutation (Igf2bp1^R167K/R167K) mice exert reduced inflammatory response, clinical scores, and joint destruction. At a molecular level, citrullination of IGF2BP1 promotes the stability of SEMA3D mRNA by promoting the interaction between IGF2BP1 and its cofactor ELAV-like protein 1 (ELAVL1), thereby promoting the invasiveness of RA-FLSs. In this study, a new citrullinated protein of IGF2BP1 is discovered, and the molecular mechanism of its citrullinated modification promoting the progression of RA disease is elucidated, which provides theoretical basis for the diagnosis and treatment of RA.

Objective Erythropoietin (EPO) known as an erythrocyte-stimulating factor is increased in patients with rheumatoid arthritis (RA). Nevertheless, the function of EPO in the process of RA and relative mechanism needs to be further clarified. Methods The level of EPO in serum and synovial fluid from patients with RA and healthy controls was determined by . Collagen-induced arthritis (CIA) mice were constructed to confirm the role of EPO on RA pathogenesis. Differentially expressed genes (DEGs) of EPO-treated fibroblast-like synoviocyte (FLS) were screened by transcriptome sequencing. The transcription factor of neuraminidase 3 (NEU3) of DEGs was verified by double luciferase reporting experiment, DNA pulldown, electrophoretic mobility shift assay and chromatin immunoprecipitation-quantitative PCR (qPCR) assay. Results The overexpression of EPO was confirmed in patients with RA, which was positively associated with Disease Activity Score 28-joint count. Additionally, EPO intervention could significantly aggravate the joint destruction in CIA models. The upregulation of NEU3 was screened and verified by transcriptome sequencing and qPCR in EPO-treated FLS, and signal transducer and activator of transcription 5 was screened and verified to be the specific transcription factor of NEU3. EPO upregulates NEU3 expression via activating the Janus kinase 2 (JAK2)-STAT5 signalling pathway through its receptor EPOR, thereby to promote the desialylation through enhancing the migration and invasion ability of FLS, which is verified by JAK2 inhibitor and NEU3 inhibitor. Conclusion EPO, as a proinflammatory factor, accelerates the process of RA through transcriptional upregulation of the expression of NEU3 by JAK2/STAT5 pathway.

Objective Triggering receptors expressed on myeloid cells-1 (TREM-1) has been shown to participate in inflammatory autoimmune diseases. Nevertheless, the detailed underlying mechanisms and therapeutic benefits by targeting TREM-1 remain elusive, especially in myeloid dendritic cells (mDCs) and systemic lupus erythematosus (SLE). Disorders of epigenetic processes including non-coding RNAs give rise to SLE, resulting in complicated syndromes. Here, we aim to address this issue and explore the miRNA to inhibit the activation of mDCs and alleviate the progress of SLE by targeting TREM-1 signal axis. Methods Bioinformatics methods were used to analyze the differentially expressed genes (DEGs) between patients with SLE and healthy individuals by four mRNA microarray datasets from Gene Expression Omnibus (GEO). Then we identified the expression of TREM-1 and its soluble form (sTREM-1) in clinical samples by ELISA, quantitative real-time PCR and Western blot. Phenotypic and functional changes of mDCs elicited by TREM-1 agonist were determined. Three databases of miRNAs target prediction and a dual-luciferase reporter assay were used to screen and verify miRNAs that can directly inhibit TREM-1 expression in vitro. Moreover, pristane-induced lupus mice were injected with miR-150-5p agomir to evaluate the effects of miR-150-5p on mDCs in lymphatic organs and disease activity in vivo. Results We screened TREM-1 as one of the hub genes closely correlated with the progression of SLE and identified sTREM-1 in serum as a valuable diagnostic biomarker for SLE. Moreover, activation of TREM-1 by its agonist promoted activation and chemotaxis of mDCs and increased the production of inflammatory cytokines and chemokines, showing higher expression of IL-6, TNF-α, and MCP-1. We showed that lupus mice displayed a unique miRNA signature in spleen, among which miR-150 was the most significantly expressed miRNA that targeting TREM-1 compared with wild type group. Transfection of miRNA-150-5p mimics directly suppressed the expression of TREM-1 by binding to its 3' UTR. Our in vivo experiments first indicated that administration of miR-150-5p agomir effectively ameliorated lupus symptoms. Intriguingly, miR-150 inhibited the over activation of mDCs through TREM-1 signal pathway in lymphatic organs and renal tissues. Conclusions TREM-1 represents a potentially novel therapeutic target and we identify miR-150-5p as one of the mechanisms to alleviate lupus disease, which is attributable for inhibiting mDCs activation through TREM-1 signaling pathway.

Objective: Sialylation of the crystallizable fragment (Fc) of ACPAs, which is catalysed by β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) could attenuate inflammation of RA. In this study, we screened the transcription factor of ST6GAL1 and elucidated the mechanism of transcriptionally upregulating sialylation of ACPAs in B cells to explore its role in the progression of RA. Methods: Transcription factors interacting with the P2 promoter of ST6GAL1 were screened by DNA pull-down and liquid chromatography with tandem mass spectrometry (LC-MS/MS), and verified by chromatin immunoprecipitation (ChIP), dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). The function of the CCCTC-binding factor (CTCF) on the expression of ST6GAL1 and the inflammatory effect of ACPAs were verified by knocking down and overexpressing CTCF in B cells. The CIA model was constructed from B cell–specific CTCF knockout mice to explore the effect of CTCF on arthritis progression. Results: We observed that the levels of ST6GAL1 and ACPAs sialylation decreased in the serum of RA patients and were negatively correlated with DAS28 scores. Subsequently, CTCF was screened and verified as the transcription factor interacting with the P2 promoter of ST6GAL1, which enhances the sialylation of ACPAs, thus weakening the inflammatory activity of ACPAs. Furthermore, the above results were also verified in the CIA model constructed from B cell–specific CTCF knockout mice. Conclusion: CCCTC-binding factor is the specific transcription factor of β-galactoside α-2,6-sialyltransferase 1 in B cells that upregulates the sialylation of ACPAs in RA and attenuates the disease progression.