Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines [i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ], chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines [i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β] involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in in vitro studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a “continuum” of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.

https://www.frontiersin.org/articles/10.3389/fimmu.2022.867260/pdf

The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis

Objectives We appraised the methodological and reporting quality of randomised controlled clinical trials (RCTs) evaluating the efficacy and safety of Chinese herbal medicine (CHM) in patients with rheumatoid arthritis (RA). Design For this systematic review, electronic databases were searched from inception until June 2015. The search was limited to humans and non-case report studies, but was not limited by language, year of publication or type of publication. Two independent reviewers selected RCTs, evaluating CHM in RA (herbals and decoctions). Descriptive statistics were used to report on risk of bias and their adherence to reporting standards. Multivariable logistic regression analysis was performed to determine study characteristics associated with high or unclear risk of bias. Results Out of 2342 unique citations, we selected 119 RCTs including 18 919 patients: 10 108 patients received CHM alone and 6550 received one of 11 treatment combinations. A high risk of bias was observed across all domains: 21% had a high risk for selection bias (11% from sequence generation and 30% from allocation concealment), 85% for performance bias, 89% for detection bias, 4% for attrition bias and 40% for reporting bias. In multivariable analysis, fewer authors were associated with selection bias (allocation concealment), performance bias and attrition bias, and earlier year of publication and funding source not reported or disclosed were associated with selection bias (sequence generation). Studies published in non-English language were associated with reporting bias. Poor adherence to recommended reporting standards ( Limitations Study quality and data extraction were performed by one reviewer and cross-checked by a second reviewer. Translation to English was performed by one reviewer in 85% of the included studies. Conclusions Studies evaluating CHM often fail to meet expected methodological criteria, and high-quality evidence is lacking.

https://bmjopen.bmj.com/content/bmjopen/7/3/e013242.full.pdf

Systematic review of the methodological quality of controlled trials evaluating Chinese herbal medicine in patients with rheumatoid arthritis.

Astragalus polysaccharide: a review of its immunomodulatory effect

Cinnamaldehyde (CA), as an active compound isolated from the bark of Cinnamomum cassia, has been reported to possess the anti-fungal, anti-bacterial, anti-inflammatory, anti-mutagenic, and anti-oxidant properties. However, the possible effects and underlying mechanisms of CA on rheumatoid arthritis (RA) have not been revealed yet. In the present study, we found that CA obviously improved the type II collagen-induced RA in rats, accompanied with decreasing pro-inflammatory factors, proliferation and metastasis. In addition, CA decreased the expression levels of TNF-α, IL-1β, and IL-6 in RA-FLSs. Besides, CA remarkably inhibited the proliferation, downregulated the EdU-positive cells, and promoted apoptosis of RA-FLSs by CCK-8, EdU and flow cytometry analysis. Moreover, the results of wound healing, transwell migration and invasion assays showed that CA inhibited the migration and invasion of RA-FLSs. Further, western blot experiment showed CA inhibited the activation of PI3K/AKT signaling pathway in RA-FLSs. Finally, 740Y-P, the PI3K/AKT signaling pathway activator, could reverse the effects of CA on the proliferation and metastasis in RA-FLSs. In conclusion, we confirmed that CA exhibited potential therapeutic properties against RA via suppressing proliferation and metastasis of RA-FLSs by blockage of PI3K/AKT signaling pathway. Therefore, our study provides evidence that CA may emerge as a therapeutic option for RA treatment.

Cinnamaldehyde Attenuates the Progression of Rheumatoid Arthritis through Down-Regulation of PI3K/AKT Signaling Pathway.

BACKGROUND Lung ischemia/reperfusion injury (LIRI) is a medical problem featuring pulmonary dysfunction and damage. The present study aimed to investigate the protective effects of erythropoietin (EPO), which has been reported to be an anti-inflammatory agent, on LIRI through inhibiting the TLR-4/NF-κB signaling pathway. MATERIAL AND METHODS All rats were randomly divided into 3 groups (n=8): a control group, a vehicle+LIRI group, and an EPO+LIRI group. LIRI included 90-min ischemia and 120-min reperfusion, while RhEpo was administered (3 kU/kg) intraperitoneally 2 h before the operation. Levels of pulmonary inflammatory responses were examined by analyzing pulmonary permeability index (PPI), oxygenation index, histology, and expressions of inflammatory cytokines. RESULTS Pretreatment with EPO significantly decreased lung W/D ratio, BALF leukocytes count and percentage, and PPI but increased oxygenation index compared with the LIRI group (P<0.05). More importantly, with EPO pretreatment there was less pathological damage compared with the vehicle group. Expressions of inflammatory cytokines (TNF-α, IL-6, and IL-1β) in the serum were significantly lower in the EPO group than in the LIRI group (P<0.05). In addition, gene expression and protein expression of TLR-4 and NF-κB were significantly inhibited with EPO pretreatment compared with the LIRI group (P<0.05). CONCLUSIONS Our study id the first to report that EPO protects lung injuries after LIRI through inhibiting the TLR4-NF-κB signaling pathway, which provides solid evidence for the use of EPO as a therapeutic agent for treating LIRI in the future.

Pretreatment with Erythropoietin Attenuates Lung Ischemia/Reperfusion Injury via Toll-Like Receptor-4/Nuclear Factor-κB (TLR4/NF-κB) Pathway.

Use of Xinfeng capsule to treat abarticular pathologic changes in patients with rheumatoid arthritis

BACKGROUND Rheumatoid arthritis (RA) is a chronic autoimmune disease targeting joints. This research aimed to explore the effects of Xinfeng capsules (XFC) on cardiac injury in adjuvant arthritis (AA) model rats and assessed the associated mechanism. MATERIAL AND METHODS An adjuvant arthritis (AA) rat model was established by intracutaneously injection with Freund's complete adjuvant (FCA). Model rats were divided into 4 groups: an AA model group, an astragalus polysaccharides (APS) group, a methotrexate (MTX) group, and an XFC and triptolide (TPT) group. Hematoxylin-eosin (HE) staining was used to observe histopathologic changes. TUNEL assay was utilized to evaluate the apoptosis of cardiomyocytes. ELISA was utilized to evaluate levels of tumor necrosis factor alpha (TNF-alpha), interleukin 17 (IL-17), and interleukin 6 (IL-6) in myocardial tissues. Quantitative RT-PCR (qRT-PCR) was used to detect microRNA-21 (miRNA21) levels. Mitogen-activated protein kinase (MAPK)/p38, Toll-like receptor 4 (TLR4), and nuclear kappa B (NF-kappaB)/p65 levels were evaluated using Western blot. RESULTS XFC significantly improved proinflammatory response compared to the AA model group (p<0.05). XFC treatment significantly decreased the number of cells staining TUNEL-positive compared with the model group (p<0.05). XFC treatment significantly reduced TNF-alpha, IL-17, and IL-6 levels in myocardial tissues compared to the model group (p<0.05). Levels of miRNA21 were significantly lower in the XFC group compared to the AA model group (p<0.05). TLR4, MAPK/p38, and NF-kappaB/p65 expression levels were significantly lower in the XFC group than in the model group (p<0.05). CONCLUSIONS Xinfeng capsule, a traditional Chinese medicine preparation, protects against cardiac injury in AA rats by modulating proinflammatory cytokines expression via the TLR4/MAPK/NF-kappaB signaling pathway.

/pdf/a-novel-chinese-medicine-xinfeng-capsule-modulates-3i4qegay5j.pdf

A Novel Chinese Medicine, Xinfeng Capsule, Modulates Proinflammatory Cytokines via Regulating the Toll-Like Receptor 4 (TLR4)/Mitogen-Activated Protein Kinase (MAPK)/Nuclear Kappa B (NF-κB) Signaling Pathway in an Adjuvant Arthritis Rat Model.

Yunxiang Cao

Papers

Use of Xinfeng capsule to treat abarticular pathologic changes in patients with rheumatoid arthritis

A Novel Chinese Medicine, Xinfeng Capsule, Modulates Proinflammatory Cytokines via Regulating the Toll-Like Receptor 4 (TLR4)/Mitogen-Activated Protein Kinase (MAPK)/Nuclear Kappa B (NF-κB) Signaling Pathway in an Adjuvant Arthritis Rat Model.

Wilforlide A ameliorates the progression of rheumatoid arthritis by inhibiting M1 macrophage polarization