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Objective: COVID-19 induces the development of autoimmune diseases, including SLE, which are characterised by inflammation, autoantibodies and thrombosis. However, the effects of COVID-19 on SLE remain unclear., Methods: We investigated the effects of COVID-19 on SLE development and progression in three animal models. Plasmids encoding SARS-CoV-2 spike protein and ACE2 receptor were injected into R848-induced BALB/C lupus mice, R848-induced IL-1 receptor antagonist knockout (KO) lupus mice and MRL/lpr mice. Serum levels of albumin and autoantibodies, lymphocyte phenotypes and tissue histology were evaluated., Results: In R848-induced BALB/C lupus mice, the SARS-CoV-2 spike protein increased autoantibody and albumin levels compared with vehicle and mock treatments. These mice also exhibited splenomegaly, which was further exacerbated by the spike protein. Flow cytometric analysis revealed elevated T helper 1 cell counts, and histological analysis indicated increased levels of the fibrosis marker protein α-smooth muscle actin. In KO mice, the spike protein induced splenomegaly, severe kidney damage and pronounced lung fibrosis. In the MRL/lpr group, spike protein increased the serum levels of autoantibodies, albumin and the thrombosis marker chemokine (C-X-C motif) ligand 4., Conclusion: COVID-19 accelerated the development and progression of lupus by inducing autoantibody production, fibrosis and thrombosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Osteoarthritis (OA) involves cartilage degeneration, thereby causing inflammation and pain. Cardiovascular diseases, such as dyslipidemia, are risk factors for OA; however, the mechanism is unclear. We investigated the effect of dyslipidemia on the development of OA. Treatment of cartilage cells with low-density lipoprotein (LDL) enhanced abnormal autophagy but suppressed normal autophagy and reduced the activity of transcription factor EB (TFEB), which is important for the function of lysosomes. Treatment of LDL-exposed chondrocytes with rapamycin, which activates TFEB, restored normal autophagy. Also, LDL enhanced the inflammatory death of chondrocytes, an effect reversed by rapamycin. In an animal model of hyperlipidemia-associated OA, dyslipidemia accelerated the development of OA, an effect reversed by treatment with a statin, an anti-dyslipidemia drug, or rapamycin, which activates TFEB. Dyslipidemia reduced the autophagic flux and induced necroptosis in the cartilage tissue of patients with OA. The levels of triglycerides, LDL, and total cholesterol were increased in patients with OA compared to those without OA. The C-reactive protein level of patients with dyslipidemia was higher than that of those without dyslipidemia after total knee replacement arthroplasty. In conclusion, oxidized LDL, an important risk factor of dyslipidemia, inhibited the activity of TFEB and reduced the autophagic flux, thereby inducing necroptosis in chondrocytes., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2024. The Korean Association of Immunologists.)

Early detection and surgical treatment are essential to achieve a good outcome in gastric cancer (GC). Stage IV and recurrent GC have a poor prognosis. Therefore, new treatments for GC are needed. We investigated the intestinal microbiome of GC patients and attempted to reverse the immunosuppression of the immune and cancer cells of GC patients through the modulation of microbiome metabolites. We evaluated the levels of programmed death-ligand 1 (PD-L1) and interleukin (IL)-10 in the peripheral blood immunocytes of GC patients. Cancer tissues were obtained from patients who underwent surgical resection of GC, and stained sections of cancer tissues were visualized via confocal microscopy. The intestinal microbiome was analyzed using stool samples of healthy individuals and GC patients. Patient-derived avatar model was developed by injecting peripheral blood mononuclear cells (PBMCs) from advanced GC (AGC) patients into NSG mice, followed by injection of AGS cells. PD-L1 and IL-10 had higher expression levels in immune cells of GC patients than in those of healthy controls. The levels of immunosuppressive factors were increased in the immune and tumor cells of tumor tissues of GC patients. The abundances of Faecalibacterium and Bifidobacterium in the intestinal flora were lower in GC patients than in healthy individuals. Butyrate, a representative microbiome metabolite, suppressed the expression levels of PD-L1 and IL-10 in immune cells. In addition, the PBMCs of AGC patients showed increased levels of immunosuppressive factors in the avatar mouse model. Butyrate inhibited tumor growth in mice. Restoration of the intestinal microbiome and its metabolic functions inhibit tumor growth and reverse the immunosuppression due to increased PD-L1 and IL-10 levels in PBMCs and tumor cells of GC patients.

Background: Interleukin (IL)-10-producing B (B10) cells are generated in response to signals from the tumor microenvironment and promote tumor growth by interacting with B10 cells. We investigated the distributions of immune cells in peripheral blood and tumor tissue samples from patients with gastric cancer (GC)., Methods: Patients with GC who underwent radical gastrectomy in Seoul St. Mary's Hospital between August 2020 and May 2021 were enrolled in this study. Forty-two samples of peripheral blood were collected, and a pair of gastric mucosal samples (normal and cancerous mucosa; did not influence tumor diagnosis or staging) was collected from each patient after surgery. B10 cells in peripheral blood and cancer mucosa samples were investigated by flow cytometry and immunofluorescence. AGS cells, gastric cancer cell line, were cultured with IL-10 and measured cell death and cytokine secretion. Also, AGS cells were co-cultured with CD19 + B cells and measured cytokine secretion., Results: The population of B10 cells was significantly larger in the blood of patients with GC compared with controls. In confocal images of gastric mucosal tissues, cancerous mucosa contained more B10 cells than normal mucosa. The population of B10 cells in cancerous mucosa increased with cancer stage. When AGS cells were cultured under cell-death conditions, cellular necrosis was significantly decreased, and proliferation was increased, for 1 day after IL-10 stimulation. Tumor necrosis factor (TNF)-α, IL-8, IL-1β, and vascular endothelial growth factor secretion by cancer cells was significantly increased by coculture of AGS cells with GC-derived CD19 + B cells., Conclusions: B cells may be one of the populations that promote carcinogenesis by inducing the production of inflammatory mediators, such as IL-10, in GC. Targeting B10 cells activity could improve the outcomes of antitumor immunotherapy. Video Abstract., (© 2023. The Author(s).)

Background: Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease that leads to joint destruction and functional disability due to the targeting of self-antigens present in the synovium, cartilage, and bone. RA is caused by a number of complex factors, including genetics, environment, dietary habits, and altered intestinal microbial flora. Microorganisms in the gut bind to nod-like receptors and Toll-like receptors to regulate the immune system and produce various metabolites, such as short-chain fatty acids (SCFAs) that interact directly with the host. Faecalibacterium prausnitzii is a representative bacterium that produces butyrate, a well-known immunomodulatory agent in the body, and this microbe exerts anti-inflammatory effects in autoimmune diseases., Methods: In this study, F. prausnitzii was administered in a mouse model of RA, to investigate RA pathology and changes in the intestinal microbial flora. Using collagen-induced arthritic mice, which is a representative animal model of RA, we administered F. prausnitzii orally for 7 weeks., Results: The arthritis score and joint tissue damage were decreased in the mice administered F. prausnitzii compared with the vehicle-treated group. In addition, administration of F. prausnitzii reduced the abundance of systemic immune cells that secrete the pro-inflammatory cytokine IL-17 and induced changes in SCFA concentrations and the intestinal microbial flora composition. It also resulted in decreased lactate and acetate concentrations, an increased butyrate concentration, and altered compositions of bacteria known to exacerbate or improve RA., Conclusion: These results suggest that F. prausnitzii exerts a therapeutic effect on RA by regulation of IL-17 producing cells. In addition, F. prausnitzii modify the microbial flora composition and short chain fatty acids in experimental RA mouse model., (© 2023. The Author(s).)

Background: Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammation of the exocrine gland. An imbalance of gut microbiota has been linked to SS. However, the molecular mechanism is unclear. We investigated the effects of Lactobacillus acidophilus (L. acidophilus) and propionate on the development and progression of SS in mouse model., Methods: We compared the gut microbiomes of young and old mice. We administered L. acidophilus and propionate up to 24 weeks. The saliva flow rate and the histopathology of the salivary glands were investigated, and the effects of propionate on the STIM1-STING signaling pathway were evaluated in vitro., Results: Lactobacillaceae and Lactobacillus were decreased in aged mice. SS symptoms were ameliorated by L. acidophilus. The abundance of propionate-producing bacterial was increased by L. acidophilus. Propionate ameliorated the development and progression of SS by inhibiting the STIM1-STING signaling pathway., Conclusions: The findings suggest that Lactobacillus acidophilus and propionate have therapeutic potential for SS. Video Abstract., (© 2023. The Author(s).)

Rheumatoid arthritis (RA) is an autoimmune disease that causes joint swelling and inflammation and can involve the entire body. RA is characterized by the increase of pro-inflammatory cytokines such as interleukin (IL) and tumor necrosis factor, and the over-activation of T lymphocytes and B lymphocytes, which may lead to severe chronic inflammation of joints. However, despite numerous studies the pathogenesis and treatment of RA remain unresolved. This study investigated the use of small heterodimer partner-interacting leucine zipper protein (SMILE) overexpression to treat a mouse model of RA. SMILE is an insulin-inducible corepressor through adenosine monophosphate-activated kinase (AMPK) signaling pathway. The injection of a SMILE overexpression vector to mice with collagen induced-arthritis resulted in a milder clinical pathology and a reduced incidence of arthritis, less joint tissue damage, and lower levels of Th17 cells and plasma B cells in the spleen. Immunohistochemistry of the joint tissue showed that SMILE decreased B-cell activating factor (BAFF) receptor (BAFF-R), mTOR, and STAT3 expression but increased AMPK expression. In SMILE-overexpressing transgenic mice with collagen antibody-induced arthritis (CAIA), a decrease in the arthritis score and reductions in tissue damage, the number of B cells, and antibody production were observed. The treatment of immune cells in vitro with curcumin, a known SMILE-inducing agent, led to decreases in plasma B cells, germinal center B cells, IL-17-producing B cells, and BAFF-R-positive B cells. Taken together, our findings demonstrate the therapeutic potential of SMILE in RA, based on its inhibition of B cell activation mediated by the AMPK/mTOR and STAT3 signaling pathway and BAFF-R expression. Video abstract., (© 2023. The Author(s).)

Introduction: Although tumor, node, metastasis (TNM) staging has been used for prognostic assessment of gastric cancer (GC), the prognosis may vary among patients with the same TNM stage. Recently, the TNM-Immune (TNM-I) classification staging system has been used for prognostic assessment of colorectal cancer based on intra-tumor T-cell status, which is a superior prognostic factor compared with the American Joint Committee on Cancer staging manual. However, an immunoscoring system with prognostic significance for GC has not been established., Method: Here, we evaluated immune phenotypes in cancer and normal tissues, then examined correlations between tissues and peripheral blood. GC patients who underwent gastrectomy at Seoul St. Mary's Hospital between February 2000 and May 2021 were included. We collected 43 peripheral blood samples preoperatively and a pair of gastric mucosal samples postoperatively, including normal and cancer mucosa, which did not influence tumor diagnosis and staging. Tissue microarray samples of GC were collected from 136 patients during surgery. We investigated correlations of immune phenotypes between tissues and peripheral blood using immunofluorescence imaging and flow cytometry, respectively. GC mucosa exhibited an increased number of CD4 + T cells, as well as increased expression levels of immunosuppressive markers (e.g., programmed death-ligand-1 [PD-L1], cytotoxic T lymphocyte antigen-4 [CTLA-4], and interleukin-10), in CD4+ T cells and non-T cells., Result: The expression levels of immunosuppressive markers were significantly increased in cancer tissues and peripheral blood mononuclear cells. In gastric mucosal tissues and peripheral blood of GC patients, similar immunosuppression phenotypes were observed, including increased numbers of PD-L1- and CTLA-4-positive T cells., Discussion: Therefore, peripheral blood analysis may be an important tool for prognostic assessment of GC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Kim, Woo, Lee, Jhun, Moon, Jung, Cho and Song.)

Interleukin-1β (IL-1β) is one of the most potent pro-inflammatory cytokines implicated in a wide range of autoinflammatory, autoimmune, infectious, and degenerative diseases. Therefore, many researchers have focused on developing therapeutic molecules that inhibit IL-1β-IL-1 receptor 1 (IL-1R1) interaction for the treatment of IL-1-related diseases. Among IL-1-related diseases, osteoarthritis (OA), is characterized by progressive cartilage destruction, chondrocyte inflammation, and extracellular matrix (ECM) degradation. Tannic acid (TA) has been proposed to have multiple beneficial effects, including anti-inflammatory, anti-oxidant, and anti-tumor activities. However, it is unclear whether TA plays a role in anti-IL-1β activity by blocking IL-1β-IL-1R1 interaction in OA. In this study, we report the anti-IL-1β activity of TA in the progression of OA in both in vitro human OA chondrocytes and in vivo rat OA models. Herein, using-ELISA-based screening, natural compound candidates capable of inhibiting the IL-1β-IL-1R1 interaction were identified. Among selected candidates, TA showed hindering IL-1β-IL-1R1 interaction by direct binding to IL-1β using surface plasmon resonance (SPR) assay. In addition, TA inhibited IL-1β bioactivity in HEK-Blue IL-1-dependent reporter cell line. TA also inhibited IL-1β-induced expression of inducible nitric oxide synthase (NOS2), cyclooxygenase-2 (COX-2), IL-6, tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in human OA chondrocytes. Moreover, TA downregulated IL-1β-stimulated matrix metalloproteinase (MMP)3, MMP13, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)4, and ADAMTS5, while upregulating collagen type II (COL2A1) and aggrecan (ACAN). Mechanistically, we confirmed that TA suppressed IL-1β-induced MAPK and NF-κB activation. The protective effects of TA were also observed in a monosodium iodoacetamide (MIA)-induced rat OA model by reducing pain and cartilage degradation and inhibiting IL-1β-mediated inflammation. Collectively, our results provide evidence that TA plays a potential role in OA and IL-1β-related diseases by hindering IL-1β-IL-1R1 interaction and suppressing IL-1β bioactivity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Dysbiosis is an environmental factor that affects the induction of axial spondyloarthritis (axSpA) pathogenesis. In the present study, we investigated differences in the gut microbiota of patients with axSpA and revealed an association between specific gut microbiota and their metabolites, and SpA pathogenesis., Method: Using 16S rRNA sequencing data derived from feces samples of 33 axSpA patients and 20 healthy controls (HCs), we examined the compositions of their gut microbiomes., Results: As a result, axSpA patients were found to have decreased α-diversity compared to HCs, indicating that axSpA patients have less diverse microbiomes. In particular, at the species level, Bacteroides and Streptococcus were more abundant in axSpA patients than in HCs, whereas Faecalibacterium (F). prausnitzii , a butyrate-producing bacteria, was more abundant in HCs. Thus, we decided to investigate whether F. prausnitzii was associated with health conditions by inoculating F. prausnitzii (0.1, 1, and 10 μg/mL) or by administrating butyrate (0.5 mM) into CD4 + T cells derived from axSpA patients. The levels of IL-17A and IL-10 in the CD4 + T cell culture media were then measured. We also assessed osteoclast formation by administrating butyrate to the axSpA-derived peripheral blood mononuclear cells. The CD4 + IL-17A + T cell differentiation, IL-17A levels were decreased, whereas IL-10 was increased by F. prausnitzii inoculation. Butyrate reduced CD4 + IL-17A + T cell differentiation and osteoclastogenesis., Discussion: We found that CD4 + IL-17A + T cell polarization was reduced, when F. prausnitzii or butyrate were introduced into curdlan-induced SpA mice or CD4 + T cells of axSpA patient. Consistently, butyrate treatment was associated with the reduction of arthritis scores and inflammation levels in SpA mice. Taken together, we concluded that the reduced abundance of butyrate-producing microbes, particularly F. prausnitzii , may be associated with axSpA pathogenesis., Competing Interests: Authors HS, T-SS, and Y-KK were employed by MD Healthcare Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Min, Na, Jhun, Lee, Choi, Park, Lee, Um, Lee, Seo, Shin, Kim, Lee, Kwok, Cho and Park.)

Obesity is a medical term used to describe an over-accumulation of adipose tissue. It causes abnormal physiological and pathological processes in the body. Obesity is associated with systemic inflammation and abnormalities in immune cell function. Rebamipide, an amino acid derivative of 2-(1H)-quinolinone, has been used as a therapeutic for the protection from mucosal damage. Our previous studies have demonstrated that rebamipide treatment regulates lipid metabolism and inflammation, leading to prevention of weight gain in high-fat diet mice. In this study, mice were put on a high calorie diet for 11 weeks while receiving injections of rebamipide. Rebamipide treatment reduced the body weight, liver weight and blood glucose levels compared to control mice and reduced both glucose and insulin resistance. Fat accumulation has been shown to cause pro-inflammatory activity in mice. Treatment with rebamipide decreased the prevalence of inflammatory cells such as Th2, Th17 and M1 macrophages and increased anti-inflammatory Treg and M2 macrophages in epididymal fat tissue. Additionally, rebamipide addition inhibited adipocyte differentiation in 3T3-L1 cell lines. Taken together, our study demonstrates that rebamipide treatment is a novel and effective method to prevent diet-induced obesity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright: © 2022 Jhun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Local inflammation in the joint is considered to contribute to osteoarthritis (OA) progression. Here, we describe an immunomodulating nanoparticle for OA treatment. Intradermal injection of lipid nanoparticles (LNPs) loaded with type II collagen (Col II) and rapamycin (LNP-Col II-R) into OA mice effectively induced Col II-specific anti-inflammatory regulatory T cells, substantially increased anti-inflammatory cytokine expression, and reduced inflammatory immune cells and proinflammatory cytokine expression in the joints. Consequently, LNP-Col II-R injection inhibited chondrocyte apoptosis and cartilage matrix degradation and relieved pain, while injection of LNPs loaded with a control peptide and rapamycin did not induce these events. Adoptive transfer of CD4 + CD25 + T cells isolated from LNP-Col II-R-injected mice suggested that T regs induced by LNP-Col II-R injection were likely responsible for the therapeutic effects. Collectively, this study suggests nanoparticle-mediated immunomodulation in the joint as a simple and effective treatment for OA.

Osteoarthritis (OA) reduces the quality of life as a result of the pain caused by continuous joint destruction. Inactivated Lactobacillus (LA-1) ameliorated osteoarthritis and protected cartilage by modulating inflammation. In this study, we evaluated the mechanism by which live LA-1 ameliorated OA. To investigate the effect of live LA-1 on OA progression, we administered LA-1 into monosodium iodoacetate (MIA)-induced OA animals. The pain threshold, cartilage damage, and inflammation of the joint synovial membrane were improved by live LA-1. Furthermore, the analysis of intestinal tissues and feces in the disease model has been shown to affect the systems of the intestinal system and improve the microbiome environment. Interestingly, inflammation of the intestinal tissue was reduced, and the intestinal microbiome was altered by live LA-1. Live LA-1 administration led to an increase in the level of Faecalibacterium which is a short-chain fatty acid (SCFA) butyrate-producing bacteria. The daily supply of butyrate, a bacterial SCFA, showed a tendency to decrease necroptosis, a type of abnormal cell death, by inducing autophagy and reversing impaired autophagy by the inflammatory environment. These results suggest that OA is modulated by changes in the gut microbiome, suggesting that activation of autophagy can reduce aberrant cell death. In summary, live LA-1 or butyrate ameliorates OA progression by modulating the gut environment and autophagic flux. Our findings suggest the regulation of the gut microenvironment as a therapeutic target for OA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cho, Na, Jhun, Woo, Lee, Lee, Lee, Um, Kim, Park and Cho.)

Osteoarthritis (OA) is the most common form of arthritis associated with ageing. Vitamin D has diverse biological effect on bone and cartilage, and observational studies have suggested it potential benefit in OA progression and inflammation process. However, the effect of vitamin D on OA is still contradictory. Here, we investigated the therapeutic potential of vitamin D in OA. Six-week-old male Wistar rats were injected with monosodium iodoacetate (MIA) to induce OA. Pain severity, cartilage destruction, and inflammation were measured in MIA-induced OA rats. Autophagy activity and mitochondrial function were also measured. Vitamin-D (1,25(OH) 2 D3) and celecoxib were used to treat MIA-induced OA rats and OA chondrocytes. Oral supplementation of vitamin D resulted in significant attenuations in OA pain, inflammation, and cartilage destruction. Interestingly, the expressions of MMP-13, IL-1β, and MCP-1 in synovial tissues were remarkably attenuated by vitamin D treatment, suggesting its potential to attenuate synovitis in OA. Vitamin D treatment in OA chondrocytes resulted in autophagy induction in human OA chondrocytes and increased expression of TFEB, but not LC3B, caspase-1 and -3, in inflamed synovium. Vitamin D and celecoxib showed a synergistic effect on antinociceptive and chondroprotective properties in vivo . Vitamin D showed the chondroprotective and antinociceptive property in OA rats. Autophagy induction by vitamin D treatment may be a promising treatment strategy in OA patients especially presenting vitamin D deficiency. Autophagy promoting strategy may attenuate OA progression through protecting cells from damage and inflammatory cell death., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2022. The Korean Association of Immunologists.)

Background: Graft-versus-host disease (GvHD) is a critical complication after allogeneic hematopoietic stem cell transplantation (HSCT). The immunosuppressants given to patients undergoing allogeneic HSCT disturb the microbiome and the host immune system, potentially leading to dysbiosis and inflammation, and may affect immune function and bone marrow transplantation. The intestinal microbiome is a target for the development of novel therapies for GvHD. Lactobacillus species are widely used supplements to induce production of antimicrobial and anti-inflammatory factors., Methods: We determined the effect of the combination of Lactobacillus acidophilus and FK506 on GvHD following major histocompatibility complex-mismatched bone marrow transplantation., Results: The combination treatment suppressed IFN-γ and IL-17-producing T cell differentiation, but increased Foxp3 + Treg differentiation and IL-10 production. Also, the combination treatment and combination treated-induced Treg cells modulated the proliferation of murine alloreactive T cells in vitro. Additionally, the combination treatment upregulated Treg-related genes-Nt5e, Foxp3, Ikzf2, Nrp1 and Itgb8-in murine CD4 + -T cells. The combination treatment also alleviated GvHD clinically and histopathologically by controlling the effector T cell and Treg balance in vivo. Moreover, the combination treatment decreased Th17 differentiation significantly and significantly upregulated Foxp3 and IL-10 expression in peripheral blood mononuclear cells from healthy controls and liver transplantation (LT) patients., Conclusions: Therefore, the combination of L. acidophilus and FK506 is effective and safe for patients undergoing allogeneic hematopoietic stem cell transplantation., (© 2022. The Author(s).)

Abbreviations: LT, liver transplantation; HCC, hepatocellular carcinoma; IS, immunosuppressants; DC, dendritic cells; Treg, regulatory T; Th17, T helper 17; AST, aspartate transaminase; ALT, alanine transaminase; OUT, operational taxonomic unit; LEfSe, linear discriminant analysis effect size; LDA, linear discriminant analysis; IL, interleukin; TGF, transforming growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; TNF-α, tumor necrosis factor-α; MIP-1α, macrophage inflammatory protein-1α; IP-10, interferon γ-induced protein; MCP-1, monocyte chemoattractant protein-1; ACR, acute cellular rejection; NF-κB, nuclear factor κB; PT INR, prothrombin time; QC, quality check; PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; ELISA, enzyme-linked immunosorbent assay.

The green-lipped mussel (GLM) contains novel omega-3 polyunsaturated fatty acids, which exhibit anti-inflammatory and joint-protecting properties. Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive loss of cartilage; oxidative stress plays a role in the pathogenesis of OA. The objectives of this study were to investigate the in vivo effects of the GLM on pain severity and cartilage degeneration using an experimental rat OA model, and to explore the mode of action of GLM. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) into the knee. Oral GLM was initiated on the day after 3dyas of MIA injection. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Samples were analyzed both macroscopically and histologically. Immunohistochemistry was used to investigate the expression of interleukin-1β (IL-1β), IL-6, nitrotyrosine, and inducible nitric oxide synthase (iNOS) in knee joints. Also, the GLM was applied to OA chondrocyte, and the expression on catabolic marker and necroptosis factor were evaluated by real-time polymerase chain reaction. Administration of the GLM improved pain levels by preventing cartilage damage and inflammation. GLM significantly attenuated the expression levels of mRNAs encoding matrix metalloproteinase-3 (MMP-3), MMP-13, and ADAMTS5 in IL-1β-stimulated human OA chondrocytes. GLM decreased the expression levels of the necroptosis mediators RIPK1, RIPK3, and the mixed lineage kinase domain-like protein (MLKL) in IL-1β-stimulated human OA chondrocytes. Thus, GLM reduced pain and cartilage degeneration in rats with experimentally induced OA. The chondroprotective properties of GLM included suppression of oxidative damage and inhibition of catabolic factors implicated in the pathogenesis of OA cartilage damage. We suggest that GLM may usefully treat human OA., Competing Interests: The authors have declared that no competing interests exist.

The potential therapeutic effects of probiotic bacteria in rheumatoid arthritis (RA) remain controversial. Thus, this study aimed to discover potential therapeutic bacteria based on the relationship between the gut microbiome and rheumatoid factor (RF) in RA. Bacterial genomic DNA was extracted from the fecal samples of 93 RA patients and 16 healthy subjects. Microbiota profiling was conducted through 16S rRNA sequencing and bioinformatics analyses. The effects of Bifidobacterium strains on human peripheral blood mononuclear cells and collagen-induced arthritis (CIA) mice were assessed. Significant differences in gut microbiota composition were observed in patients with different RF levels. The relative abundance of Bifidobacterium and Collinsella was lower in RF-high than in RF-low and RF-negative RA patients, while the relative abundance of Clostridium of Ruminococcaceae family was higher in RF-high than in RF-low and RF-negative patients. Among 10 differentially abundant Bifidobacterium , B. longum RAPO exhibited the strongest ability to inhibit IL-17 secretion. Oral administration of B. longum RAPO in CIA mice, obese CIA, and humanized avatar model significantly reduced RA incidence, arthritis score, inflammation, bone damage, cartilage damage, Th17 cells, and inflammatory cytokine secretion. Additionally, B. longum RAPO significantly inhibited Th17 cells and Th17-related genes- IL-17A , IRF4 , RORC , IL-21 , and IL-23R -in the PBMCs of rheumatoid arthritis patients. Our findings suggest that B. longum RAPO may alleviate RA by inhibiting the production of IL-17 and other proinflammatory mediators. The safety and efficacy of B. longum RAPO in patients with RA and other autoimmune disorders merit further investigation., Competing Interests: Authors YJ, S-JP, MP, BK and GJ was employed by company BIFIDO Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jeong, Jhun, Lee, Na, Choi, Cho, Lee, Lee, Park, You, Kim, Park, Kwon, Cho, Ji and Park.)

Small heterodimer partner interacting leucine zipper protein (SMILE) is an orphan nuclear receptor and a member of the bZIP family of proteins. We investigated the mechanism by which SMILE suppressed the development of inflammatory bowel disease (IBD) using a DSS-induced colitis mouse model and peripheral blood mononuclear cells (PBMCs) from patients with ulcerative colitis (UC). Metformin, an antidiabetic drug and an inducer of AMPK, upregulated the level of SMILE in human intestinal epithelial cells and the number of SMILE-expressing cells in colon tissues from DSS-induced colitis mice compared to control mice. Overexpression of SMILE using a DNA vector reduced the severity of DSS-induced colitis and colitis-associated intestinal fibrosis compared to mock vector. Furthermore, SMILE transgenic mice showed ameliorated DSS-induced colitis compared with wild-type mice. The mRNA levels of SMILE and Foxp3 were downregulated and SMILE expression was positively correlated with Foxp3 in PBMCs from patients with UC and an inflamed mucosa. Metformin increased the levels of SMILE, AMPK, and Foxp3 but decreased the number of interleukin (IL)-17-producing T cells among PBMCs from patients with UC. These data suggest that SMILE exerts a therapeutic effect on IBD by modulating IL-17 production., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yang, Park, Hwang, Cho, Na, Choi, Jhun, Kim, Lee, Park and Cho.)

Osteoarthritis (OA) is the most common form of arthritis and age-related degenerative joint disorder, which adversely affects quality of life and causes disability. However, the pathogenesis of OA remains unclear. This study was performed to examine the effects of Lactobacillus rhamnosus in OA progression. OA was induced in 6-week-old male Wistar rats by monosodium iodoacetate (MIA) injection, and the effects of oral administration of L. rhamnosus were examined in this OA rat model. Pain severity, cartilage destruction, and inflammation were measured in MIA-induced OA rats. The small intestines were isolated from OA rats, and the intestinal structure and inflammation were measured. Protein expression in the dorsal root ganglion was analyzed by immunohistochemistry. The effects of L. rhamnosus on mRNA and protein expression in chondrocytes stimulated with interleukin (IL)-1β and lipopolysaccharide (LPS) were analyzed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Pain severity was decreased in L. rhamnosus -treated MIA-induced OA rats. The levels of expression of MCP-1, a potential inflammatory cytokine, and its receptor, CCR2, were decreased, and GABA and PPAR-γ expression were increased in L. rhamnosus -treated OA rats. The inflammation, as determined by IL-1β, and cartilage destruction, as determined by MMP3, were also significantly decreased by L. rhamnosus in OA rats. Additionally, intestinal damage and inflammation were improved by L. rhamnosus. In human OA chondrocytes, TIMP1, TIMP3, SOX9, and COL2A1 which are tissue inhibitors of MMP, and IL-10, an anti-inflammatory cytokine, were increased by L. rhamnosus . L. rhamnosus treatment led to decreased pain severity and cartilage destruction in a rat model of OA. Intestinal damage and inflammation were also decreased by L. rhamnosus treatment. Our findings suggested the therapeutic potential of L. rhamnosus in OA.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important transcription factor that plays a pivotal role in cellular defense against oxidative injury. Nrf2 signaling is involved in attenuating autoimmune disorders such as rheumatoid arthritis (RA). B cells play several roles in the pathogenesis of RA, such as in autoantibody production, antigen presentation, and T-cell activation. We investigated the anti-arthritic mechanisms of sulforaphane, an activator of Nrf2, in terms of its effect on B cells. To investigate the effect of sulforaphane on collagen-induced arthritis (CIA), sulforaphane was administered intraperitoneally after CIA induction. Hematoxylin and eosin-stained sections were scored for inflammation, pannus invasion, and bone and cartilage damage. We assessed the expression levels of inflammation-related factors by real-time PCR and the levels of various IgG subclasses by enzyme-linked immunosorbent assay. Sulforaphane treatment reduced the arthritis score and the severity of histologic inflammation in CIA mice. The joints from sulforaphane-treated CIA mice showed decreased expression of interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, receptor activator of NF-κB ligand, and tartrate-resistant acid phosphatase. Sulforaphane-treated mice showed lower circulating levels of type-II-collagen-specific IgG, IgG1, and IgG2a. In vitro, sulforaphane treatment significantly reduced the differentiation of lipopolysaccharide-stimulated murine splenocytes into plasma B cells and germinal-center B cells. Finally, sulforaphane significantly inhibited the production of IL-6, TNF-α, and IL-17 by human peripheral blood mononuclear cells stimulated with an anti-CD3 monoclonal antibody in a dose-dependent manner. Inhibition of differentiation into plasma B and Germinal Center B cells may be the mechanism underlying the anti-arthritic effect of sulforaphane., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article.

Obesity, a condition characterized by excessive accumulation of body fat, is a metabolic disorder related to an increased risk of chronic inflammation. Obesity is mediated by signal transducer and activator of transcription (STAT) 3, which is regulated by genes associated with retinoid-interferon-induced mortality (GRIM) 19, a protein ubiquitously expressed in various human tissues. In this study, we investigated the role of GRIM19 in diet-induced obese C57BL/6 mice via intravenous or intramuscular administration of a plasmid encoding GRIM19. Splenocytes from wild-type and GRIM19-overexpressing mice were compared using enzyme-linked immunoassay, real-time polymerase chain reaction, Western blotting, flow cytometry, and histological analyses. GRIM19 attenuated the progression of obesity by regulating STAT3 activity and enhancing brown adipose tissue (BAT) differentiation. GRIM19 regulated the differentiation of mouse-derived 3T3-L1 preadipocytes into adipocytes, while modulating gene expression in white adipose tissue (WAT) and BAT. GRIM19 overexpression reduced diet-induced obesity and enhanced glucose and lipid metabolism in the liver. Moreover, GRIM19 overexpression reduced WAT differentiation and induced BAT differentiation in obese mice. GRIM19-transgenic mice exhibited reduced mitochondrial superoxide levels and a reciprocal balance between Th17 and Treg cells. These results suggest that GRIM19 attenuates the progression of obesity by controlling adipocyte differentiation.

Coenzyme Q10 (CoQ10), also known as ubiquinone, is a fat-soluble antioxidant. Although CoQ10 has not been approved as medication by the Food and Drug Administration, it is widely used in dietary supplements. Some studies have shown that CoQ10 has anti-inflammatory effects on various autoimmune disorders. In this study, we investigated the anti-inflammatory effects of liposome/gold hybrid nanoparticles encoded with CoQ10 (LGNP-CoQ10). Both CoQ10 and LGNP-CoQ10 were administered orally to mice with collagen-induced arthritis (CIA) for 10 weeks. The inflammation pathology of joint tissues of CIA mice was then analyzed using hematoxylin and eosin and Safranin O staining, as well as immunohistochemistry analysis. We obtained immunofluorescence staining images of spleen tissues using confocal microscopy. We found that pro-inflammatory cytokines were significantly decreased in LGNP-CoQ10 injected mice. Th17 cell and phosphorylated STAT3-expressed cell populations were also decreased in LGNP-CoQ10 injected mice. When human peripheral blood mononuclear cells (PBMCs) were treated with CoQ10 and LGNP-CoQ10, the IL-17 expression of PBMCs in the LGNP-CoQ10-treated group was significantly reduced. Together, these results suggest that LGNP-CoQ10 has therapeutic potential for the treatment of rheumatoid arthritis., Competing Interests: The authors have declared that no competing interests exist.

The protein encoded by the Gene Associated with Retinoid-Interferon-Induced Mortality-19 (GRIM-19) is located in the mitochondrial inner membrane and is homologous to the NADH dehydrogenase 1-alpha subcomplex subunit 13 of the electron transport chain. Multiple sclerosis (MS) is a demyelinating disease that damages the brain and spinal cord. Although both the cause and mechanism of MS progression remain unclear, it is accepted that an immune disorder is involved. We explored whether GRIM-19 ameliorated MS by increasing the levels of inflammatory cytokines and immune cells; we used a mouse model of experimental autoimmune encephalomyelitis (EAE) to this end. Six-to-eight-week-old male C57BL/6, IFNγ-knockout (KO), and GRIM-19 transgenic mice were used; EAE was induced in all strains. A GRIM-19 overexpression vector (GRIM19 OVN) was electrophoretically injected intravenously. The levels of Th1 and Th17 cells were measured via flow cytometry, immunofluorescence, and immunohistochemical analysis. IL-17A and IFNγ expression levels were assessed via ELISA and quantitative PCR. IL-17A expression decreased and IFNγ expression increased in EAE mice that received injections of the GRIM19 OVN. GRIM-19 transgenic mice expressed more IFNγ than did wild-type mice; this inhibited EAE development. However, the effect of GRIM-19 overexpression on the EAE of IFNγ-KO mice did not differ from that of the empty vector. GRIM-19 expression was therapeutic for EAE mice, elevating the IFNγ level. GRIM-19 regulated the Th17/Treg cell balance., Competing Interests: Conflicts of Interests: The authors declare no potential conflicts of interest., (Copyright © 2020. The Korean Association of Immunologists.)

Background: To evaluate the immunomodulatory effect of Lactobacillus sakei in a mouse model of rheumatoid arthritis (RA) and in human immune cells., Methods: We evaluated whether L. sakei reduced the severity of collagen-induced arthritis (CIA) and modulated interleukin (IL)-17 and IL-10 levels, as well as whether it affected the differentiation of CD4 + T cells and regulatory B cells. We evaluated osteoclastogenesis after culturing bone marrow-derived mononuclear cells with L. sakei., Results: The differentiation of T helper 17 cells and the serum level of IL-17 were suppressed by L. sakei in both human peripheral blood mononuclear cells and mouse splenocytes. The serum level of IL-10 was significantly increased in the L. sakei-treated group, whereas the regulatory T cell population was unchanged. The population of regulatory B cells significantly increased the in L. sakei-treated group. Oral administration of L. sakei reduced the arthritis incidence and score in mice with CIA. Finally, osteoclastogenesis and the mRNA levels of osteoclast-related genes were suppressed in the L. sakei-treated group., Conclusion: L. sakei exerted an anti-inflammatory effect in an animal model of RA, regulated Th17 and regulatory B cell differentiation, and suppressed osteoclastogenesis. Our findings suggest that L. sakei has therapeutic potential for RA.

Background: Rheumatoid arthritis (RA) is a long-term autoimmune disorder that mostly affects the joints and leads to the destruction of cartilage. An RA model in non-human primates is especially useful because of their close phylogenetic relationship to humans in terms of cross-reactivity to compounds developed using modern drug technologies., Methods: We used a collagen-induced arthritis (CIA) model in Macaca fascicularis. CIA was induced by the immunization of chicken type II collagen. Swelling was measured as the longitudinal and transverse axes of 16 proximal interphalangeal joints., Results: A new system for visual evaluation was created, with a perfect score of 16. Individual behavioral analysis was also conducted. Serum was collected once a week after the first immunization. Blood chemistry and inflammatory cytokine parameters were higher in the CIA group than in the wild type group., Conclusion: In conclusion, we established CIA in M. fascicularis, and the results can be used for drug evaluation models.

Background: Fibrosis is the formation of excess connective tissue in an organ or tissue during a reparative or reactive process. Graft-versus-host disease (GvHD) is a medical complication of allogeneic tissue transplantation with transplanted donor T cell-mediated inflammatory response; it is characterized by a severe immune response with fibrosis in the final stage of the inflammatory process. T helper 17 cells play a critical role in the pathogenesis of GvHD. Fingolimod (FTY720), an analogue of sphingosine-1-phosphate (S1P), is an effective immunosuppressive agent in experimental transplantation models., Methods: In this study, we evaluated the effects of FTY720 as a treatment for an animal GvHD model with inflammation and fibrosis. The splenocytes, lymph nodes, blood, tissues from Syngeneic mice and GvHD-induced mice treated vehicle or FTY720 were compared using flow cytometry, hematological analyses, histologic analyses., Results: FTY720 reduced clinical scores based on the following five clinical parameters: weight loss, posture, activity, fur texture, and skin integrity. FACS data showed that T lymphocyte numbers increased in mesenteric lymph nodes and decreased in splenocytes of FTY720-treated mice. Tissue analysis showed that FTY720 reduced skin, intestinal inflammation, and fibrotic markers. FTY720 dramatically decreased α-smooth muscle actin, connective tissue growth factor, and fibronectin protein levels in keloid skin fibroblasts., Conclusions: Thus, FTY720 suppressed migration of pathogenic T cells to target organs, reducing inflammation. FTY720 also inhibited fibrogenesis marker expression in vitro and in vivo. Together, these results suggest that FTY720 prevents GvHD progression via immunosuppression of TH17 and simultaneously acts an anti-fibrotic agent.

Osteoarthritis (OA), which is the most common degenerative joint disorder, has been considered a non-inflammatory disease with abnormal mechanics. Interleukin (IL)-17 is a pleiotropic cytokine involved in inflammatory diseases and their production is driven by the cytokine including IL-1 and IL-23. However, little is known about the mechanism of IL-17 in the development of OA. Here, we investigated the role of IL-17 in the pathogenesis of OA using monosodium iodoacetate (MIA)-injected IL-17 and IL-1 receptor antagonist (IL-1Ra) double-deficient mice. In MIA-injected IL-1Ra KO mice, nociceptive properties, degree of cartilage damage, and the level of inflammatory factors in articular cartilage were increased compared to MIA-injected wild-type mice. Interestingly, the intestinal architecture was impaired in IL-1Ra KO mice compared to wild-type mice and the damage was further exacerbated by MIA injection. Deficiency of IL-17 reduced nociceptive properties and cartilage destruction, as well as inflammation-related factors in MIA-injected IL-1Ra KO mice compared to MIA-injected wild-type mice. Furthermore, IL-17-treated chondrocytes from OA patients showed enhanced expression of catabolic factors that are involved in the destruction of cartilage in OA. IL-17 accelerates the destruction of cartilage and small intestine via regulation of several inflammatory mediators in an OA murine model. These results suggest that IL-17 plays a critical role in the development of OA., (Copyright © 2020 Na, Park, Cho, Kwon, Choi, Jhun, Kim, Park and Cho.)

Receptor-interacting serine/threonine-protein kinase (RIPK) 3 is a member of the TNF receptor-I signaling complex and mediates necroptosis, an inflammatory cell death. Ulcerative colitis (UC) is an excessive inflammatory disease caused by uncontrolled T cell activation. The current study is aimed to determine whether RIPK3 inhibitor attenuates UC development inhibiting inflammation and necroptosis using experimental colitis mice model. Dextran sulfate sodium-induced colitis mice were administered RIPK3 inhibitor (3 mg/ml) 3 times and their tissues were analyzed by immunohistochemistry. RIPK3, mixed lineage kinase domain-like (MLKL), phosphorylated MLKL, IL-17, and CD4 in colitis patient colon tissues were detected using confocal microscopy. Protein levels were measured using immunohistochemistry and ELISA. The differentiation of Th17 cells was evaluated using flow cytometry. The expression of proinflammatory cytokines and necroptosis in peripheral blood mononuclear cells from UC patients was decreased markedly by RIPK3 inhibitor treatment. We also observed that the injection of RIPK3 inhibitor improves colitis severity and protects intestinal destruction. RIPK3 inhibitor reduced necroptosis factors and proinflammatory cytokines in the colon and consequently protected colon devastation. The expression of inflammatory mediators in experimental colitis mice splenocytes was decreased significantly by RIPK3 inhibitor treatment. These results suggest that RIPK3 inhibitor ameliorates severity of experimental colitis and reduces inflammation through the inhibition of inflammatory response and necroptosis and support RIPK3-targeting substances for treatment of UC., Competing Interests: Conflicts of Interest: The authors declare no potential conflicts of interest., (Copyright © 2020. The Korean Association of Immunologists.)

Background: Lumbar disc herniation (LDH) is the most common cause of back and leg pain. We developed a specially designed needle and a minimally invasive interventional procedure to treat LDH., Objectives: Assess outcomes of procedure and describe our methodology and clinical application., Design: Case series., Setting: A chronic pain management center., Patients and Methods: Patients with LDH underwent fluoroscopically guided interventional interlaminar needling using a specially designed curved round needle. The outcome measures were evaluated three times: before the intervention and at 6 and 12 months after the intervention., Main Outcome Measures: Visual analog scale (VAS) pain score, Oswestry Disability Index (ODI)., Sample Size: 43 patients., Results: Six months after the intervention, the VAS pain score decreased by 5.1 (2.2) points and the ODI decreased by 30.7% (16.6%) compared to baseline. Twelve months after the intervention, the VAS pain score decreased by 6.2 (1.7) points and the ODI decreased by 36.9% (15.2%) compared to baseline., Conclusions: This study suggests that fluoroscopically guided interventional interlaminar needling has clinical significance in managing pain resulting from LDH., Limitations: This was an exploratory case series study. Additional studies and randomized clinical trials are needed to evaluate the efficacy of the technique compared to other treatments., Conflict of Interest: None.

Systemic lupus erythematosus (SLE) is mediated by a chronic and dysregulated inflammatory response. Interleukin (IL)-17, a proinflammatory cytokine, and T helper (Th)17 cells are associated with chronic autoimmune diseases. We hypothesized that inhibition of IL-17 would decrease the numbers of T cell subsets that function as B-cell helpers, as well as B-cell differentiation into plasma cells and autoantibody expression. The IL-17 level was increased markedly in Roquin san/san mice. Loss of IL-17 in Roquin san/san mice improved nephritis by downregulating immunoglobulin (Ig)G, IgG1, and IgG2a production. Formation of germinal centers (GCs), and follicular B- and T-cell differentiation was reduced, whereas the number of regulatory T (Treg) cells and immature B cells was increased, by IL-17 deficiency in Roquin san/san mice. These results suggest that IL-17 inhibition can ameliorate SLE by inhibiting B-cell differentiation into GCs. Therefore, IL-17-producing Th17 cells show promise as a target for development of novel therapeutics for SLE.

Background: Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by upregulation of inflammatory cell death and osteoclastogenesis. Necrostatin (NST)-1s is a chemical inhibitor of receptor-interacting serine/threonine-protein kinase (RIPK)1, which plays a role in necroptosis., Methods: We investigated whether NST-1s decreases inflammatory cell death and inflammatory responses in a mouse model of collagen-induced arthritis (CIA)., Results: NST-1s decreased the progression of CIA and the synovial expression of proinflammatory cytokines. Moreover, NST-1s treatment decreased the expression of necroptosis mediators such as RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL). In addition, NST-1s decreased osteoclastogenesis in vitro and in vivo. NST-1s downregulated T helper (Th)1 and Th17 cell expression, but promoted Th2 and regulatory T (Treg) cell expression in CIA mice., Conclusions: These results suggest that NST-1s attenuates CIA progression via the inhibition of osteoclastogenesis and might be a potential therapeutic agent for RA therapy.

Osteoarthritis (OA) is a degenerative disease that induces pain, cartilage deformation, and joint inflammation. Mesenchymal stem cells (MSCs) are potential therapeutic agents for treatment of OA. However, MSC therapy can cause excessive inflammation. Signal transducer and activator of transcription 3 (STAT3) modulates secretion of many proinflammatory cytokines. Experimental OA was induced by intra-articular (IA) injection of monosodium iodoacetate (MIA) to the right knee of rats. MSCs from OA patients (OA-MSCs) were treated with STA21, a small molecule that blocks STAT3 signaling, by IA or intravenous (IV) injection after MIA injection. Pain severity was quantified by assessment of secondary tactile allodynia using the von Frey assessment test. Cartilage degradation was measured by microcomputed tomography image analysis, histological analysis, and the Mankin score. Protein and gene expression was evaluated by enzyme-linked immunosorbent assay, immunohistochemistry, and real-time polymerase chain reaction. MSCs increased production of proinflammatory cytokines under inflammatory conditions. STA21 significantly decreased expression of these proinflammatory molecules via inhibition of STAT3 activity but increased gene expression of molecules related to migration potential and immunomodulation in OA-MSCs. STAT3-inhibited OA-MSCs administrated by IV or IA injection decreased pain severity and cartilage damage in rats with MIA-induced OA rats by decreasing proinflammatory cytokines in the joints. Combined IA and IV-injected STAT3-inhibited OA-MSCs had an additive effect of pain relief in MIA-induced OA rats. STAT3 inhibition may optimize the therapeutic activities of MSCs for treating OA by attenuating pain and progression of MIA by inhibiting inflammation and cartilage damage.

Osteoarthritis (OA), a degenerative disorder, induces pain, joint inflammation, and destruction of the articular cartilage matrix. Probiotic complex, rosavin, and zinc have been used as dietary supplements that exhibit anti-inflammatory and antioxidant properties. However, there is no evidence demonstrating a synergic effect in OA. This study aims to determine whether combination with probiotic complex, rosavin, and zinc decreases progression of monosodium iodoacetate (MIA)-induced OA rat model. The combination improved pain levels by preventing cartilage damage. The expression of proinflammatory cytokines and catabolic factors was reduced by the combination within the joint tissue. However, the combination increased anti-inflammatory cytokines as well as the anabolic factor production. The gene level of catabolic factors was decreased with treatment of the combination in chondrocytes isolated from OA patients. These results suggest that the combination can improve MIA development through the inhibition of proinflammatory cytokines and cartilage destruction, thus playing a key role as a therapeutic candidate for OA treatment.

Disruption of the balance among the microbiota, epithelial cells, and resident immune cells in the intestine is involved in the pathogenesis of inflammatory bowel disease (IBD). Probiotics exert protective effects against IBD, and probiotic commensal Lactobacillus species are common inhabitants of the natural microbiota, especially in the gut. To investigate the effects of Lactobacillus acidophilus on the development of IBD, L. acidophilus was administered orally in mice with dextran sodium sulfate (DSS)-induced colitis. DSS-induced damage and the therapeutic effect of L. acidophilus were investigated. Treatment with L. acidophilus attenuated the severity of DSS-induced colitis. Specifically, it suppressed proinflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor-α, IL-1β, and IL-17 in the colon tissues, which are produced by T helper (Th) 17 cells. Moreover, in vitro L. acidophilus treatment directly induced T regulatory (Treg) cells and the production of IL-10, whereas the production of IL-17 was suppressed in splenocytes. In addition, we found that L. acidophilus treatment decreased the levels of α-smooth muscle actin, a marker of activated myofibroblasts, and type I collagen compared with control mice. These results suggest that L. acidophilus may be a novel treatment for IBD by modulating the balance between Th17 and Treg cells, as well as fibrosis development.

Recipients of liver transplantation (LT) require long-term immunosuppressive drug treatment, but lifelong immunosuppressive treatment has severe side effects. It is known that some LT recipients develop immune tolerance, and although the development of such operational tolerance should allow a decrease in the burden of immunosuppressive drug treatment, the factors that indicate operational tolerance are not clear. This study aimed to monitor immunological markers over time in LT recipients to identify those markers indicating the development of operational tolerance. We performed a prospective pilot study measuring immune markers, including the ratio of regulatory T (Treg) and T helper (Th) 17 cells in peripheral blood in the 14 most immunologically stable patients among 70 clinically stable LT recipients. The doses of immunosuppressive drugs given to these 14 LT recipients were tapered over time and they were monitored for immunological markers related to the development of immune tolerance. As the doses of immunosuppressive drugs were reduced, the Treg/Th17, Th1/Th17, and CD8/Th17 ratio in tolerant recipients was significantly increased compared with that of nontolerant recipients. These results suggest that monitoring of changes in the immune makers, including Treg/Th17 ratio during tapering of immunosuppression may allow prediction of the development of tolerance.

Probiotic complex, zinc, and coenzyme Q10 (CoQ10) are recognized dietary supplements with an anti-inflammatory role. Although these supplementations are individually known to benefit rheumatoid arthritis (RA), there is no evidence suggesting any synergic effect. The primary goal of this study is to determine whether probiotic complex, zinc, and CoQ10 attenuate the development of collagen-induced arthritis (CIA). The combination of probiotic complex, zinc, and CoQ10 reduced CIA severity by downregulating the levels of IgG, IgG1, and IgG2a in serum. Joint inflammation, bone destruction, and cartilage damage were also improved by the complex. There was a decrease in the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17, and vascular endothelial growth factor (VEGF) in the joint synovium. The balance between helper T 17 (Th17) cells and regulatory T (Treg) cells was shown to be controlled reciprocally by the complex. These findings suggest that the combination of probiotic complex, zinc, and CoQ10 can ameliorate the development of CIA by inhibiting the expression of proinflammatory cytokines, and is thus an important therapeutic candidate for RA treatment.

This corrects the article DOI: 10.1038/srep34617.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints. High-fat diet (HFD) is a risk factor for RA and is related to inflammation but responds minimally to medication. Given the association between HFD and inflammation, it is important to understand the function of inflammation-related T cells in RA with HFD. Collagen-induced arthritis (CIA), a model of RA, was induced in HFD mice by injection of collagen II, and metabolic markers and T cells were analyzed. The metabolic index and IgG assay results were higher in HFD-CIA mice than in nonfat diet-CIA mice. Numbers of inflammation-related T cells and macrophages, such as Th1 and Th17 cells and M1 macrophages, were higher in spleens of HFD-CIA mice. HFD-CIA mice had a high level of α 2 -glycoprotein 1 (Azgp1), a soluble protein that stimulates lipolysis. To examine the association between Azgp1 and Th17 cells, the reciprocal effects of Azgp1 and IL-17 on Th17 differentiation and lipid metabolism were measured. Interestingly, Azgp1 increased the Th17 population of splenocytes. Taken together, our data suggest that the acceleration of fat loss caused by Azgp1 in RA with metabolic syndrome is related to the increase of IL-17. Mice injected with the Azgp1-overexpression vector exhibited more severe CIA compared with the mock vector-injected mice., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Results: The oral administration of rebamipide decreased plaque formation in atherosclerotic lesions as well as the markers of metabolic disorder in ApoE-deficient mice with atherosclerosis. Pro-inflammatory cytokines were also suppressed by rebamapide. In addition, the population of Th17 was decreased, whereas Treg was increased in the spleen of rebamipide-treated ApoE deficient mice. Rebamipide also ameliorated the severity of obese arthritis and has the capability to reduce the development of atherosclerosis by controlling the balance between Th17 and Treg cells. Thus, rebamipide could be a therapeutic agent to improve the progression of inflammation in metabolic diseases.

PTEN is a tyrosine phosphatase with significant function in inhibiting STAT3 activation. Recently, inactivation of STAT3 has been demonstrated as a therapeutic candidate for autoimmune arthritis. The expression of PTEN controlled by p53 regulates autoimmune arthritis through modulating the balance between Th17 and Treg. We hypothesized that PTEN regulated by p53 might reduce CIA severity and inflammatory response via inhibiting STAT3 activation. Our results revealed that PTEN could ameliorate experimental autoimmune arthritis by reducing STAT3 activity and Th17 differentiation. Systemic infusion of PTEN overexpression downregulated CIA severity. In addition, PTEN overexpression decreased the activation of T cells and modulated reciprocal differentiation of Th17 and Treg cells. We observed that PTEN expression downregulated by p53 deficiency induced the activation of STAT3. Loss of p53 exacerbated autoimmune arthritis and dysregulated the population of Th17 and Treg. These data suggest that induction of STAT3-modulatory activity of PTEN may be a therapeutic target for rheumatoid arthritis therapy.

Background: Hepatitis B (HB) is an infectious disease with unfavorable consequence for patients and involved in chronic inflammation of liver. The present study aimed to investigate whether High-mobility group protein B (HMGB)1/receptor for advanced glycation end products (RAGE) aggravates inflammation enhancing the expression of interleukin (IL)-17., Methods: Mild and severe HB liver tissue and peripheral blood samples were obtained intra-operatively. Histological analysis of the livers was performed by immunohistochemistry. IL-1β and IL-6 of liver tissue were detected by confocal microscopy staining. Relative mRNA expression was measured by real-time PCR and protein levels were measured by enzyme-linked immunosorbent assay., Results: HMGB1, RAGE and IL-17 expression is increased in liver of HB patients with acute on chronic liver failure (ACLF) compared to healthy controls. HMGB1 treatment induced inflammatory cytokines including IL-17 in peripheral blood cells of HB patients. IL-17 also induced the expression of RAGE and IL-1β in peripheral blood cells of HB patients with ACLF. On the other hands, the inhibitory factor of p38 and nuclear factor-kappa B reduced the expression of RAGE and IL-1β in peripheral blood cells HB patients with ACLF., Conclusions: HMGB1, RAGE and IL-17 expression is increased in liver of severe HB patients. HMGB1 and RAGE interaction may contribute to the inflammation of liver enhancing the expression of IL-17, which can be possibly restored through the decline of the HMGB1/RAGE axis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation. Red ginseng is a steamed and dried Panax ginseng C.A. Meyer, which has been used as alternative medicine for thousands of years. This study was undertaken to investigate the effects of red ginseng extracts (RGE) on autoimmune arthritis in mice and humans and to delineate the underlying mechanism. RGE was orally administered three times a week to mice with arthritis. Oral administration of RGE markedly ameliorated clinical arthritis score and histologically assessed joint inflammation in mice with CIA. A significant reduction in STAT3 phosphorylation and a decrease in the number of Th17 cells were observed with RGE treatment. There was also a marked reduction in RANKL-induced osteoclastogenesis with treatment of RGE. The inhibitory effect of RGE on Th17 differentiation and osteoclastogenesis observed in mice was also confirmed in the subsequent experiments performed using human peripheral blood mononuclear cells. Our findings provide the first evidence that RGE can regulate Th17 and reciprocally promote Treg cells by inhibiting the phosphorylation of STAT3. Therefore, RGE can ameliorate arthritis in mice with CIA by targeting pathogenic Th17 and osteoclast differentiation, suggesting a novel therapy for treatment of RA.