Treatment failures in rheumatoid arthritis (RA) leads to undesirable morbidity associated with immunosuppression. Recent studies of synovial tissue from refractory RA patients highlight the role of sy Show more
Treatment failures in rheumatoid arthritis (RA) leads to undesirable morbidity associated with immunosuppression. Recent studies of synovial tissue from refractory RA patients highlight the role of synovial fibroblasts and vascular endothelium in driving treatment failure. Utilizing high-dimensional spatial transcriptomics, we uncovered a crucial role for neurotrophin signaling in driving abnormal vascular maturation in RA synovia. Neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3), induce differentiation of synovial fibroblasts into mural cells - pericytes and vascular smooth muscle cells. Mechanistically, NOTCH3 signaling activates a cascade of neurotrophin signaling through transcriptional induction of NGFR, a co-receptor for NGF. In RA synovial tissue explants, stimulation with NGF, BDNF, or NT3 leads to a dramatic increase in maturation of synovial tissue vasculature. Conversely, pharmacologic inhibition with neurotrophin inhibitors drastically abolished maturation of vascularization in RA synovial explants. Notably, the FDA-approved tropomyosin receptor kinase (TRK) inhibitors larotrectinib and entrectinib effectively reverse synovial vascular maturation in human RA tissue explants.Our findings suggest that fibroblast-derived neurotrophin signaling is a critical pathway in sustaining mature blood vessels in RA synovia, and that neurotrophin inhibitors reverse abnormal vascular maturation in RA. In rheumatoid arthritis, fibroblast neurotrophin signaling drives abnormal vascular maturation by inducing differentiation of fibroblasts into vascular mural cells. Show less
The role of chemokines in motor abnormalities (MAs) in first-episode psychosis (FEP) is underexplored. Investigating immune biomarker levels in FEP, their association with MAs, and their differences w Show more
The role of chemokines in motor abnormalities (MAs) in first-episode psychosis (FEP) is underexplored. Investigating immune biomarker levels in FEP, their association with MAs, and their differences with individuals without FEP may reveal therapeutic targets. Thirty-eight patients and thirty-four controls were included. Primary outcomes assessed group differences in chemokines related immune whole blood biomarkers, including innate (CCL2, CCL3, and CCL11), compensatory (PPARα, CXCL1, and CB2), natural immune chemotaxis biomarkers (CXCL2 and CXCR4), and growth factors (LPAR2, brain-derived neurotrophic factor [BDNF], and vascular endothelial growth factor [VEGF]). Our secondary aim was to examine their association with the total score of five motor scales: the Neurological Evaluation Scale (NES), Simpson Angus Scale (SAS), catatonia symptom of the Comprehensive Assessment of Symptoms and History (CASH), Barnes Akathisia Rating Scale, and Unified Parkinson's Disease Rating Scale (UPDRS). We found significantly higher levels of protein markers (CCL2, VEGF, and CXCL12) and mRNA expression (CXCR4, PPARα, CB2, and LPAR2) in FEP patients compared to the control group. We only observed positive and significant results for CCL2-UPDRS total and CXCR4-SAS associations in post hoc multivariate analyses (β = 0.401, p = 0.036 and β = 0.58, p = 0.001, respectively). Elevated levels of potential neurotoxic (CCL2) and neuroprotective (PPARα and CB2) biomarkers were seen in FEP patients when compared to controls. Moreover, CCL2 levels seem to be directly associated with Parkinsonism in FEP patients, while CXCR4 may be protective against extrapyramidal symptoms. Further research should clarify immune differences between FEP and non-FEP groups, especially in chemotaxis and endocannabinoid pathways. Show less