Pyroptosis is crucial to rheumatoid arthritis (RA) by inducing and aggravating inflammation. TNF-α is abundant in fibroblast-like synoviocytes of RA (RA-FLSs) and plays a key role in pyroptosis by inducing nuclear factor (NF)-κB activation. Additionally, interleukin (IL)-37 is involved in autoimmune diseases as an anti-inflammatory cytokine and innate and acquired immune response inhibitor. However, the effect of IL-37 on pyroptosis in RA-FLSs remains unclear. Therefore, this study investigated the effects and mechanism of IL-37 on RA-FLS pyroptosis induced by TNF-α. In this study, the serum cytokines in patients with RA and healthy controls were detected using ELISA. The RA-FLSs were then cultured with TNF-α, with or without various IL-37 concentrations, to test the cytokine levels in the cell supernatant. 5-Ethynyl-2'-Deoxyuridine (EdU) assay assessed the effects of IL-37 on RA FLS proliferation. RA-FLS apoptosis was assessed using flow cytometry and mitochondrial membrane potential (MMP) measurement. In addition, transmission electron microscopy (TEM) was used to examine cell pyroptosis. We selected the optimal concentration for the following experiments and detected the signal pathway of IL-37 on pyroptosis of RA FLSs by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blotting. Finally, we validated the therapeutic effects of IL-37 on CIA rat model in vivo. IL-37 inhibited inflammation in vitro and in vivo and reduced pyroptosis-related protein expression in RA FLSs. Furthermore, we determined that nuclear factor κB (NF-κB) signaling is required for GSDMD-mediated pyroptosis in RA FLSs. IL-37 alleviates TNF-α-induced pyroptosis of RA FLSs by inhibiting NF-κB/GSDMD signaling. Additionally, our data revealed a novel mechanism for IL-37 in RA FLSs, suggesting a new potential therapy for IL-37 to treat RA.

The G protein–coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver–bile acid–microbiota–organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non–small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for β-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR–β-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.

Objective: Interstitial lung disease (ILD) is a common manifestation of connective tissue disease (CTD) that manifests as several subtypes with significant differences in prognosis. It is necessary to evaluate the efficacy and safety of pirfenidone (PFD) combined with immunosuppressant (IS) in the treatment of CTD-ILD. Methods: A total of 111 patients with CTD-ILD were enrolled, including those with systemic sclerosis (SSc), inflammatory myopathy (IIM), rheumatoid arthritis (RA), and other CTDs (such as systemic lupus erythematosus, primary Sjogren's syndrome, and undifferentiated CTD). After evaluation of the high-resolution computed tomography (HRCT), pulmonary function (PF), and basic disease activity, patients either were or were not prescribed PFD and were followed up regularly for 24 weeks. Results: After 24 weeks of treatment, predicted forced vital capacity (FVC%) in the SSc-PFD group had improved by 6.60%, whereas this value was 0.55% in patients with SSc-no-PFD. The elevation in FVC% was also significant in IIM-PFD over the IIM-no-PFD controls (7.50 vs. 1.00%). The predicted diffusing capacity for carbon monoxide (DLCo%) of RA-PFD was enhanced by 7.40%, whereas that of RA-no-PFD decreased by 5.50%. When performing a subtype analysis of HRCT images, the change in FVC% among patients with SSc with a tendency toward usual interstitial pneumonia (UIP) was higher in those given PFD (SSc-PFD-UIP) than the no-PFD group (8.05 vs. −3.20%). However, in IIM patients with a non-UIP tendency, PFD displayed better therapeutic effects than the control (10.50 vs. 1.00%). DLCo% improved significantly in patients with the PFD-treated RA-non-UIP subtype compared with the patients with no-PFD (10.40 vs. −4.45%). Dichotomizing the patients around a baseline FVC% or DLCo% value of 70%, the PFD arm had a more improved FVC% than the no-PFD arm within the high-baseline-FVC% subgroups of patients with SSc and IIM (6.60 vs. 0.10%, 6.30 vs. 1.10%). In patients with RA-PFD, DLCo% showed a significant increase in the subgroup with low baseline DLCo% compared to that in patients with RA-no-PFD (7.40 vs. −6.60%). Conclusion: The response of PF to PFD varied between CTD-ILD subsets. Patients with SSc and IIM showed obvious improvements in FVC%, especially patients with SSc-UIP and IIM-non-UIP. In RA, the subsets of patients with non-UIP and a lower baseline DLCo% most benefited from PFD.

Background: This study is to investigate the expression of progranulin (PGRN) in systemic lupus erythematosus (SLE) patients and the effect of glucocorticoid (GC) treatment on its expression.Methods: Thirty newly diagnosed severe SLE patients and 30 healthy subjects were enrolled in this study. The serum levels of PGRN and the inflammatory factors of SLE were detected by ELISA and the mRNA expression of these proteins were detected by real-time PCR.Results: The serum levels of PGRN, IL-6, PR3, TNFR, TNF-α and anti-dsDNA antibody in SLE patients were increased significantly compared with healthy controls (P < 0.05). The relative expression of PGRN mRNA was increased by 4.88-fold in pre-treatment SLE patients compared with controls (P < 0.05). After prednisone treatment, the serum levels of PGRN decreased significantly, and the relative expression of PGRN mRNA was decreased by 1.34-fold compared with the untreated controls (P < 0.01). Moreover, Serum concentration of PGRN was correlated with serum levels of IL-6, TNF-α, TNFR and anti-dsDNA antibody in both pre-treatment and post-treatment SLE patients.Conclusions: PGRN is up-regulated in the SLE patients and is correlated with pro-inflammatory cytokines and anti-dsDNA antibody. Glucocorticoids can down-regulate the expression of PGRN in SLE patients.Virtual slides: http://www.diagnosticpathology.diagnomx.eu/vs/1562484036905973

Introduction: TNFα is a proinflammatory cytokine that plays a central role in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of certolizumab pegol, a TNFα blocker, on endothelial cell function and angiogenesis. Methods: Human dermal microvascular endothelial cells (HMVECs) were stimulated with TNFα with or without certolizumab pegol. TNFα-induced adhesion molecule expression and angiogenic chemokine secretion were measured by cell surface ELISA and angiogenic chemokine ELISA, respectively. We also examined the effect of certolizumab pegol on TNFα-induced myeloid human promyelocytic leukemia (HL-60) cell adhesion to HMVECs, as well as blood vessels in RA synovial tissue using the Stamper-Woodruff assay. Lastly, we performed HMVEC chemotaxis, and tube formation. Results: Certolizumab pegol significantly blocked TNFα-induced HMVEC cell surface angiogenic E-selectin, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression and angiogenic chemokine secretion (P < 0.05). We found that certolizumab pegol significantly inhibited TNFα-induced HL-60 cell adhesion to HMVECs (P < 0.05), and blocked HL-60 cell adhesion to RA synovial tissue vasculature (P < 0.05). TNFα also enhanced HMVEC chemotaxis compared with the negative control group (P < 0.05) and this chemotactic response was significantly reduced by certolizumab pegol (P < 0.05). Certolizumab pegol inhibited TNFα-induced HMVEC tube formation on Matrigel (P < 0.05). Conclusion: Our data support the hypothesis that certolizumab pegol inhibits TNFα-dependent leukocyte adhesion and angiogenesis, probably via inhibition of angiogenic adhesion molecule expression and angiogenic chemokine secretion.

Autoimmune diseases are affected by complex pathophysiology involving several cell types, cytokines, antibodies, and mimicking factors. Different drugs are used to ameliorate these autoimmune reactions, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antiantibodies, and small molecular drugs (DMARDs), and they are clinically in vogue for diseases such as rheumatoid arthritis (RA). Nevertheless, low cost-effectiveness, reduced efficacy, adverse effects, and patient nonresponse are unappealing factors driving the development of new drugs such as iguratimod. Iguratimod is primarily used to ameliorate RA in Japanese and Chinese clinics. However, its efficacy against other autoimmune ailments is also under intense investigation, and the number of investigations is becoming increasingly larger with each passing day. The articular structure comprises synovium, ligaments, and bone. The latter is more complex than the others since it regulates blood cells and autoimmunity in addition to providing skeletal support to the body. Therefore, its protection is also of prime importance in RA and other autoimmune diseases. Herein, we have highlighted the role of iguratimod in autoimmune diseases and bone protection. We suggest that iguratimod’s unique mode of action compared with that of other DMARDs and its good patient response makes it a suitable antirheumatic and bone-protecting drug.