Severe dengue manifestations caused by the dengue virus are a global health problem. Studies suggest that severe dengue disease depends on uncontrolled immune cell activation, and excessive inflammation adds to the pathogenesis of severe dengue disease. Therefore, it is important to understand the process that triggers the uncontrolled activation of the immune cells. The change in immune response in mild to severe dengue may be due to direct virus-to-cell interaction or it could be a contact-independent process through the extracellular vesicles (EVs) released from infected cells. The importance of circulating EVs in the context of dengue virus infection and pathogenesis remains unexplored. Therefore, understanding the possible biological function of circulating EVs may help to delineate the role of EVs in the progression of disease. Our present study highlights that EVs from plasma of severe dengue patients can have immunosuppressive properties on CD4+ T cells which may contribute to T cell suppression and may contribute to dengue disease progression.

CD44 partcipates in multiple inflammatory reactions. Here, we aimed to investigate the role of CD44 and the ligand, hyaluronan (HA), on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) pathogenesis. We found that CD44 was universally expressed in CD4+ lymphocytes in the peripheral blood of CP/CPPS patients. After silencing CD44 expression or delivering 4-methylumbelliferone (4-MU), the pain severity and prostatic inflammation were significantly relieved. In vitro assay found that HA/CD44 was able to regulate T helper 1 (Th1) cells differentiation, the deficiency of which diminished experimental autoimmune prostatitis (EAP) susceptibility. Bioinformatic analysis suggested that after HA or 4-MU treatment, mTOR signaling was significantly altered, and these results were confirmed by subsequent Western blotting assay. Besides, mass spectrometry and co-immunoprecipitation assays found that CD44 was able to interact with Annexin A1 (ANX A1), and this kind of interaction stabilized ANX A1 protein and maintained the activation of Akt/mTOR pathway. Meanwhile, HA-treatment-enhanced prostatic inflammation, Th1 cell differentiation, and Akt/mTOR pathway activation were reversed after silencing the expression of ANX A1 using shANX A1-lentivirus. The present study systematically investigates the functional role of HA/CD44 in CP/CPPS and identifies novel mechanisms for HA/CD44 promoting Th1 cell differentiation. Targeting the HA/CD44/ANX A1/Akt/mTOR signaling represents novel potential therapeutic strategies for patients with CP/CPPS.
Copyright © 2022 Chen, Meng, Li, Li, Liu, Jin, Zhang, Hao, Chen, Zhang and Liang.

Systemic sclerosis (SSc) is a life-threatening chronic connective tissue disease with the characteristics of skin fibrosis, vascular injury, and inflammatory infiltrations. Though inhibition of phosphodiesterase 4 (PDE4) has been turned out to be an effective strategy in suppressing inflammation through promoting the accumulation of intracellular cyclic adenosine monophosphate (cAMP), little is known about the functional modes of inhibiting PDE4 by apremilast on the process of SSc. The present research aimed to investigate the therapeutic effects and underlying mechanism of apremilast on SSc. Herein, we found that apremilast could markedly ameliorate the pathological manifestations of SSc, including skin dermal thickness, deposition of collagens, and increased expression of α-SMA. Further study demonstrated that apremilast suppressed the recruitment and activation of macrophages and T cells, along with the secretion of inflammatory cytokines, which accounted for the effects of apremilast on modulating the pro-fibrotic processes. Interestingly, apremilast could dose-dependently inhibit the activation of M1 and T cells in vitro through promoting the phosphorylation of CREB. In summary, our research suggested that inhibiting PDE4 by apremilast might provide a novel therapeutic option for clinical treatment of SSc patients.
© 2021. The Author(s), under exclusive licence to CPS and SIMM.

Galectin-3 (Gal-3) has diverse roles in inflammatory and autoimmune diseases. There is evidence that Gal-3 plays a role in both type 1 and type 2 diabetes. While the role of Gal-3 expression in immune cells invading the pancreatic islets in the experimental model of type 1 diabetes mellitus has been already studied, the importance of the overexpression of Gal-3 in the target β cells is not defined. Therefore, we used multiple low doses of streptozotocin (MLD-STZ)-induced diabetes in C57Bl/6 mice to analyze the effect of transgenic (TG) overexpression of Gal-3 in β cells. Our results demonstrated that the overexpression of Gal-3 protected β cells from apoptosis and attenuated MLD-STZ-induced hyperglycemia, glycosuria, and ketonuria. The cellular analysis of pancreata and draining lymph nodes showed that Gal-3 overexpression significantly decreased the number of pro-inflammatory cells without affecting the presence of T-regulatory cells. As the application of exogenous interleukin 33 (IL-33) given from the beginning of MLD-STZ diabetes induction attenuates the development of disease, by increasing the presence of regulatory FoxP3+ ST2+ cells, we evaluated the potential synergistic effect of the exogenous IL-33 and TG overexpression of Gal-3 in β cells at the later stage of diabetogenesis. The addition of IL-33 potentiated the survival of β cells and attenuated diabetes even when administered later, after the onset of hyperglycemia (12-18 days), suggesting that protection from apoptosis and immunoregulation by IL-33 may attenuate type 1 diabetes.
Copyright © 2021 Jovicic, Petrovic, Pejnovic, Ljujic, Miletic Kovacevic, Pavlovic, Jeftic, Djukic, Srejovic, Jakovljevic and Lukic.

Hyaluronan (HA), an extracellular matrix component, accumulates in most chronic inflammatory tissues. Here, we studied the impact of HA on the pathogenesis of chronic prostatitis.First, we sorted demographic characteristics and peripheral blood serum samples from patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) to assess the relationship between the levels of HA in peripheral blood serum and the severity of inflammation in patients. Second, we induced an experimental autoimmune prostatitis (EAP) mouse model and treated the mice with 4-methylumbelliferone (4-MU) (200 mg/kg/day). After the mice were sacrificed, RNA from Th1 cells of the mouse spleens was extracted for RNA sequencing. We used weighted gene co-expression network analysis (WGCNA) to identify co-expressed gene modules and hub-gene related to the pathogenesis of EAP. The expression of critical genes associated with the identified pathway was confirmed by using western blot analysis.HA was significantly more highly expressed in CP/CPPS patients than in healthy volunteers and positively correlated with the severity of pain, urination symptoms, and quality of life. Besides, the protein expression of HA was significantly higher in prostate tissues derived from EAP models than in those derived from controls. 4-MU, an oral inhibitor of HA synthesis, relieved immunocyte infiltration to the prostate and significantly reduced the proportion of Th1 cells. Based on the WGCNA, we identified 18 co-expression modules and identified that the Grey60 and brown modules were positively associated with the EAP and negatively associated with the Control and 4-MU-treated groups. Pathway enrichment analyses and western blot assays proved that HA potentially activated the cell cycle pathway, increasing the proportion of Th1 cells promoting chronic prostatitis pathogenesis, while these processes were reversed by 4-MU treatment.Our results suggest that HA is elevated in patients with CP/CPPS compared with healthy controls and that targeting HA through 4-MU suppresses the activity of the cell cycle-related pathway, potentially by decreasing the proportion of Th1 cells and relieving chronic prostatitis. Our findings might inspire the clinical treatment of chronic prostatitis.© 2021 Wiley Periodicals LLC.