Synovial Fluid-Derived Extracellular Vesicles of Patients with Arthritides Contribute to Hippocampal Synaptic Dysfunctions and Increase with Mood Disorders Severity in Humans

Abstract

Arthritides are a highly heterogeneous group of disorders that include two major clinical entities, localized joint disorders such as osteoarthritis (OA) and systemic autoimmune-driven diseases such as rheumatoid arthritis (RA). Arthritides are characterized by chronic debilitating musculoskeletal conditions and systemic chronic inflammation. Poor mental health is also one of the most common comorbidities of arthritides. Depressive symptoms which are most prevalent, negatively impact patient global assessment diminishing the probability of achieving the target of clinical remission. Here, we investigated new insights into mechanisms that link different joint disorders to poor mental health, and to this issue, we explored the action of the synovial fluid-derived extracellular vesicles (EVs) on neuronal function. Our data show that the exposure of neurons to different concentrations of EVs derived from both RA and OA synovial fluids (RA-EVs and OA-EVs) leads to increased excitatory synaptic transmission but acts on specific modifications on excitatory or inhibitory synapses, as evidenced by electrophysiological and confocal experiments carried out in hippocampal cultures. The treatment of neurons with EVs membrane is also responsible for generating similar effects to those found with intact EVs suggesting that changes in neuronal ability arise upon EVs membrane molecules' interactions with neurons. In humans with arthritides, we found that nearly half of patients (37.5%) showed clinically significant psychiatric symptoms (CGIs score ≥ 3), and at least mild anxiety (HAM-A ≥ 7) or depression (MADRS and HAM-D ≥ 7); interestingly, these individuals revealed an increased concentration of synovial EVs. In conclusion, our data showing opposite changes at the excitatory and inhibitory levels in neurons treated with OA- and RA-EVs, lay the scientific basis for personalized medicine in OA and RA patients, and identify EVs as new potential actionable biomarkers in patients with OA/RA with poor mental health.

Synovial fluid extracellular vesicles as arthritis biomarkers: the added value of lipid-profiling and integrated omics

“…Furthermore, the dominance of neutrophil-derived EVs in SF of RA was also confirmed by Foers et al, describing 45 proteins significantly elevated in SF EVs of RA patients with high levels of inflammation compared to low levels of inflammation, while 135 proteins were significantly elevated compared to SF EVs of OA patients, with proteins associated with "neutrophil degranulation" (42/135 proteins) being significantly enriched in SF EVs of RA patients with high levels of inflammation [77] . Overall, RA SF EVs prominently feature markers of the neutrophil lineage and their granule proteins, e.g., the neutrophil azurophilic granule protein, myeloperoxidase (MPO) detected at concentrations nearly nine times higher in severely inflamed RA joints compared to their mildly inflamed counterparts [77] . Similarly, post-translationally modified proteins, such as citrullinated and carbamylated proteins [79] , have been strongly associated with RA and have been proposed as biomarkers.…”

“…Likewise, EV research in RA has proved instrumental to the determination of molecular characteristics that differentiate RA from OA or the normal phenotype [Figure 3]. In patients with RA, SF contains EVs at concentrations higher than SF from OA patients [76,77] . Although the amount of protein of SF EVs of RA exceeds that in OA, in both SF sources, CD177 (neutrophils), CD14 (monocytes), CD62E (activated epithelium), and CD25 (T-reg cells) have been discovered [78] .…”

“…Intrinsically, EVs have been shown to be associated with citrullinated proteins, including fibrinogen D fragment, Sp alpha (like CD5 antigen protein) receptor, and fibrinogen beta chain precursor, among others [80] . Furthermore, cathepsin G (CTSG) and Ras-related C3 botulinum toxin substrate 1 (RAC1), which are pivotal for T cell responses, FLS activation, and ROS generation, were shown to be upregulated in RA-affected joints with high and low levels of inflammation, respectively [77] .…”

Depressive and Anxiety Disorders in Patients with Inflammatory Bowel Diseases: Are There Any Gender Differences?

“…Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions characterized by intestinal and extra-intestinal symptoms (e.g., arthritis) associated with poor quality of life, especially during acute exacerbations [ 1 , 2 ]. The course of IBD can be complicated by comorbidities such as immune-mediated illnesses including dermatological, ocular, and articular disease, or conditions characterized by inflammatory dysregulation such as metabolic syndrome or mental disorders [ 3 , 4 ].…”

Understanding the Interplay between Air Pollution, Biological Variables, and Major Depressive Disorder: Rationale and Study Protocol of the DeprAir Study

“…MDD is associated with abnormalities of several biological systems resulting in a dysregulation of neurotransmitters, especially of serotonin and noradrenalin [ 10 ]. In this regard, the genetic variants predisposing to MDD refer to the serotonin receptors or transporters [ 11 ], but also to genes that regulate systems outside the central nervous system (CNS), such as the skeletal one [ 12 ], thus explaining the systemic nature of the disorder and the vulnerability of depressed subjects to different medical illnesses [ 13 ]. In addition, single nucleotide polymorphisms in clock genes (i.e., those regulating sleep-wake cycles) confer a higher risk of MDD [ 14 ].…”