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Disturbed glycolipid metabolism activates CXCL13-CXCR5 axis in senescent TSCs to promote heterotopic ossification formation

ABSTRACT: Heterotopic ossification (HO) occurs as a common complication after injury, while its risk factor and mechanism remain unclear yet, which restricts the development of pharmacological treatment. Clinical research suggested that diabetes mellitus (DM) patients were prone to develop HO in tendon, but the solid evidence and mechanical research are still needed. Here, we combined the clinical samples and DM mice model to identify that disordered glycolipid metabolism aggravates the senescence of tendon derived stem cells (TSCs) and promotes their osteogenic differentiation. Then, combining the RNA-seq results of aging tendon, we detected the abnormally activated autocrine CXCL13-CXCR5 axis in TSCs cultured in high fat high glucose (HFHG) environment and also in aged tendon. Genetic inhibition of CXCL13 successfully alleviates the HO formation in DM mice, providing a potential therapeutical target for suppressing HO formation in DM patients after trauma or surgery.

ORGANISM(S): Mus musculus

PROVIDER: GSE234916 | GEO | 2024/08/28

REPOSITORIES: GEO

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Project description:BackgroundC-X-C chemokine ligand 13 (CXCL13) is frequently elevated in cerebrospinal fluid (CSF) in a variety of inflammatory central nervous system (CNS) diseases, has been detected in meningeal B cell aggregates in brain tissues of multiple sclerosis patients, and proposedly recruits B cells into the inflamed CNS. Besides B cells also follicular helper T (Tfh) cells express the cognate receptor C-X-C chemokine receptor type 5 (CXCR5) and follow CXCL13 gradients in lymphoid tissues. These highly specialized B cell helper T cells are indispensable for B cell responses to infection and vaccination and involved in autoimmune diseases. Phenotypically and functionally related circulating CXCR5+CD4 T cells occur in blood. Their co-recruitment to the inflamed CSF is feasible but unresolved.MethodsWe approached this question with a retrospective study including data of all patients between 2017 and 2019 of whom immune phenotyping data of CXCR5 expression and CSF CXCL13 concentrations were available. Discharge diagnoses and CSF laboratory parameters were retrieved from records. Patients were categorized as pyogenic/aseptic meningoencephalitis (ME, n = 29), neuroimmunological diseases (NIMM, n = 22), and non-inflammatory neurological diseases (NIND, n = 6). ANOVA models and Spearman's Rank-Order correlation were used for group comparisons and associations of CXCL13 levels with immune phenotyping data.ResultsIn fact, intrathecal CXCL13 elevations strongly correlated with CXCR5+CD4 T cell frequencies in the total cohort (p < 0.0001, r = 0.59), and ME (p = 0.003, r = 0.54) and NIMM (p = 0.043, r = 0.44) patients. Moreover, the ratio of CSF-to-peripheral blood (CSF/PB) frequencies of CXCR5+CD4 T cells strongly correlated with CXCL13 levels both in the total cohort (p = 0.001, r = 0.45) and ME subgroup (p = 0.005, r = 0.50), indicating selective accumulation. ME, NIMM and NIND groups differed with regard to CSF cell counts, albumin quotient, intrathecal IgG, CXCL13 elevations and CXCR5+CD4 T cells, which were higher in inflammatory subgroups.ConclusionThe observed link between intrathecal CXCL13 elevations and CXCR5+CD4 T cell frequencies does not prove but suggests recruitment of possible professional B cell helpers to the inflamed CSF. This highlights CSF CXCR5+CD4 T cells a key target and potential missing link to the poorly understood phenomenon of intrathecal B cell and antibody responses with relevance for infection control, chronic inflammation and CNS autoimmunity.

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Disturbed glycolipid metabolism activates CXCL13-CXCR5 axis in senescent TSCs to promote heterotopic ossification formation

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