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Acute viral myocarditis (AVMC), most often caused by coxsackievirus B3 (CVB3) infection, is characterized by myocardial inflammation associated with high morbidity and mortality. A pathogenic role for T helper (Th) 17 cells in AVMC is well established. Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been shown to play a key role in various inflammatory diseases. However, the expression of MALAT1 and its impact on Th17 cells differentiation in AVMC remain unclear. In the present study, we found that MALAT1 was highly expressed in mice with AVMC, and the expression was correlated positively with cardiac pathological scores, cardiac IL-17 mRNA expression, and the percentages of splenic Th17 cells. We further demonstrated that MALAT1 knockdown could significantly alleviate the severity of disease and inhibit the differentiation of Th17 cells, accompanying the reduced mRNA expression of RORγt and productions of Th17-related pro-inflammatory cytokines in vivo. Additionally, in vitro analysis showed that MALAT1 knockdown suppressed naïve CD4

Neutrophilic asthma (NA) is a severe type of steroid resistant asthma, and so far the immune mechanisms underlying NA are not clear. In this article, we performed a comprehensive assessment of Th-cell subsets and cytokines in severe NA patients. A total of 13 healthy individuals and 31 severe asthma patients were enrolled in this study. Refractory asthma patients were defined as those with eosinophilic asthma (EA, accounted for 32% of asthmatic patients) or NA (68%) according to sputum neutrophil/eosinophil counts or blood eosinophils. Th-cell subsets in peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry, and cytokines were detected by cytometric bead array (CBA). The results showed significant differences were observed in Th-cell phenotypes, where the number of Th1 cells were reduced and the numbers of Th2 cells were increased in NA and EA groups, respectively, when compared with healthy controls. Th17 cells were not strongly associated with severe neutrophilic asthma. The frequencies of mucosal-associated invariant T (MAIT) cells were strikingly reduced in severe asthma patients, especially in the NA group. This NA group also showed increased levels of IL-17A, IL-17F, TNF-α, and IL-6 in serum and increased levels of IL-17A, IL-17F, IFN-γ, TNF-α, IL-1β, IL-5, IL-6, and IL-8 in sputum. In addition, sputum IL-6 was positively correlated with TNF-α, IFN-γ, IL-17A, and IL-8. Our results uncovered a controversial role for Th17 cells, which were reduced in severe asthma patients. Severe neutrophilic asthma was associated with a striking deficiency of MAIT cells and high pro-inflammatory cytokine levels.

The objective was to investigate the effect of exclusive enteral nutrition (EEN) on T helper (Th) 17 cells by observing the effects of EEN on colon and serum interleukin (IL)-17A levels in juvenile inflammatory bowel disease (IBD) rat models and to reveal the potential mechanism of the therapeutic effect of EEN on IBD. ATNBS-induced IBD rat model was established. Feeding Peptison, a type of enteric nutrition (EN) for EEN-IBD group and EEN group, normal feed for IBD model group and control group for six consecutive days. Four groups of juvenile rats were sacrificed on day 7. The pathology of the intestinal mucosa was examined, the expression of IL-17A in serum was detected by ELISA, and the expression of IL-17A in intestinal tissue was detected by both western blot and real-time PCR (RT-PCR). Diarrhea, bloody stools, and weight loss were found in both the IBD group and the EEN-IBD group. After 5 days of EEN feeding, the stool characteristics, and blood in the stools of the rats in the EEN-IBD group were significantly relieved compared with those of the IBD group. There was no significant difference in the body mass growth rate between the IBD group and EEN-IBD group (P > 0.05). The growth rate of the EEN group was 51.29 ± 3.61%, which was significantly lower than that of the control group (60.17 ± 9.32%) with P < 0.05. The disease activity index (DAI) score of the EEN-IBD group was significantly lower than that of the IBD group (P < 0.05). In the IBD group, colonic congestion and edema were obvious, scattered ulcers were observed, and the intestinal mucosa had a large amount of inflammatory cell infiltration. In the EEN-IBD group, the intestinal mucosa was slightly congested and a small amount of inflammatory cell infiltrated. The serum IL-17A expression level in the IBD group was significantly higher than in the EEN-IBD group, control group, and EEN group (P < 0.05). Both the gene and protein expressions of IL-17A in the intestinal tissue of the EEN-IBD group were significantly lower than in the IBD group (P < 0.01), and it was significantly higher in the IBD group than in the control and EEN groups (P < 0.01). EEN effectively reduced the intestinal inflammation in the juvenile rats with IBD. The mechanism could be related to the regulation of Th17 cells and the expression of the corresponding cytokine, IL-17A. EEN may play a role in downregulating the expression of IL-17A in the intestinal mucosa.

To observe the inflammatory response, differentiation of Th17/Treg subsets and apoptosis of lymphocytes, by regulating miR-126 in lymphocytes of septic rats. After using cecal ligation and puncture to establish sepsis model, miR-126 mimic and miR-126 inhibitor were used to transfect lymphocytes of septic rats in vitro and in vivo. ELISA was used to detect TNF-α, IL-6, IL-17, and IL-10, the differentiation of Th17 and Treg was measured by flow cytometry, and apoptosis of lymphocytes was observed by fluorescence microscope; the changes of caspase signaling pathway were detected by immunofluorescence, PCR, and Western blotting. The result show that the expression of miR-126 increased in sepsis. After overexpression of miR-126, the release of TNF-α, IL-6, and IL-17 decreased; the release of IL-10 increased; T lymphocyte subsets differentiated toward Treg; caspase signaling pathway weakened; and lymphocyte of apoptosis decreased compared with sepsis group. While, after inhibition of miR-126, the release of TNF-α, IL-6, and IL-17 increased; the release of IL-10 decreased; T lymphocyte subsets differentiated toward TH17; caspase signaling pathway enhanced; and lymphocyte of apoptosis increased compared with sepsis group. Taken together, regulation of miR-126 can alter the inflammatory response, differentiation of T lymphocyte subsets, and apoptosis of lymphocytes in septic rats.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by demyelinating neuropathy. The etiology of MS is not yet clear and its treatment remains a major medical challenge. While we search for drugs that can effectively treat experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we also hope to further explore its possible pathogenesis. In the present study, we investigated whether methyl butyrate (MB) could alleviate EAE and its potential mechanisms. In EAE mice, we found that administration of MB was effective in alleviating their clinical signs and improving histopathological manifestations of the CNS. In the CNS and intestinal lamina propria, we observed fewer effector T cells, including Th1 and Th17, in the MB-treated group. MB also increased the proportion of regulatory T cells and the secretion of IL-10 in peripheral immune organs. In vitro, MB led to suppression of Th1 cells and promotion of regulatory T cells in their differentiation. Given that MB had no direct effect on Th17 cell differentiation in vitro, we hypothesized that MB suppressed Th17 cells indirectly by inhibiting the secretion of IL-6, which was later confirmed both in vitro and in vivo. In addition, we found that MB treatment upregulated Maf gene expression in mice, which explained its promotion of IL-10 secretion. The above findings suggest that MB may provide new ideas for the study of the mechanism of MS and have positive implications for new drug development.

Acute lung injury (ALI)/acute respiratory distress syndrome is characterized by increased pulmonary inflammation, where T helper 17 (Th17) cells play an important regulatory role. Notch signaling critically regulates Th17 differentiation and is known to be linked with proximal T cell by protein kinase C theta (PKCθ). We hypothesized that PKCθ inhibition could attenuate ALI by suppressing Th17 response via the Notch signaling pathway. Male C57BL/6 mice were treated with phosphate-buffered saline (PBS), lipopolysaccharide (LPS), LPS and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT, a Notch signaling inhibitor), or LPS and PKCθ inhibitor (PI), and the bronchoalveolar lavage fluid (BALF), blood, and lung tissues were harvested at 48 h after the LPS challenge. CD4+ T cells were treated with DAPT or PI and harvested after 72 h. PKCθ inhibition markedly attenuated pathological changes and decreased the wet to dry weight ratio of the mouse lungs. The total cell and neutrophil counts, tumor necrosis factor-α (TNF- α) in BALF, myeloperoxidase activity in lung tissue, and the leukocyte count in whole blood were markedly reduced by PKCθ inhibition. The concentration of interleukin (IL)-17 and IL-22 in BALF, and the percentage of CD4+IL-17A+ T cells in the lungs were significantly downregulated by PKCθ inhibition. A similar trend was observed for the expression of retinoic acid-related orphan receptor gamma t and IL-23 receptor after PKCθ inhibition accompanied with inactivation of the Notch signaling pathway in vivo and in vitro. Collectively, these data demonstrated that PKCθ inhibition protects against LPS-induced ALI by suppressing the differentiation and pathogenicity of Th17, at least partially, through a Notch-dependent mechanism.

Acute lung injury (ALI) is a syndrome characterized by damage to the alveolar-capillary wall, pulmonary edema and recruitment of inflammatory cells. Previous studies have indicated that aquaporin 4 (AQP4) plays a key role in brain edema formation and resolution. However, the role of AQP4 in the development and progression of ALI is not clear and needs to be resolved. In our current study, mouse ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) at a concentration of 30 mg/kg. For the inhibition of AQP4, 200 mg/kg of TGN-020 (Sigma, USA) was administered intraperitoneally every 6 h starting at 30 min before intratracheal instillation of LPS. The results of the present work indicate, for the first time, that mice treated with the AQP4 inhibitor TGN-020 had attenuated LPS-induced lung injury, reduced proinflammatory cytokine release (including IL-1α, IL-1β, IL-6, TNF-α, IL-23, and IL-17A), and an improved survival rate. Additionally, we found that the attenuated lung injury scores, increased survival rate, and decreased BALF total protein concentration in TGN-020-treated mice were all abrogated by rIL-17A administration. Furthermore, TGN-020 treatment downregulated the phosphorylation of PI3K and Akt, increased the expression of SOCS3, and decreased the expression of p-STAT3 and RORγt. In conclusion, inhibition of AQP4 by TGN-020 has a detectable protective effect against lung tissue injury induced by LPS, and this effect is associated with inhibition of IL-17A through the downregulation of the PI3K/Akt signaling pathway and upregulation of SOCS3 protein.

The pathogenesis of ulcerative colitis (UC) remains unclear, and it is believed that an imbalance of regulatory T (Treg) cells and T helper 17 (Th17) cells is related to the occurrence of UC. Curcumin has been confirmed to exert anti-inflammatory effects in bronchial asthma and osteoarthritis by regulating the balance of Treg/Th17 cells. This study aimed to explore the therapeutic potential of curcumin in dextran sulfate sodium (DSS)-induced UC rats by regulating the balance of Treg/Th17 cells. Disease activity index (DAI) scores were calculated. Changes in colon inflammation were observed using hematoxylin and eosin staining. Treg and Th17 cells in the spleen were detected by flow cytometry, and the levels of interleukin (IL)-10 and IL-17A were determined using enzyme-linked immunosorbent assay. In DSS-induced colitis, curcumin significantly ameliorated colitis symptoms by reducing the DAI and increasing colon length. Additionally, curcumin significantly increased the expression of Treg cells and decreased the expression of Th17 cells and the extent of histopathological damage. Furthermore, curcumin increased the expression of IL-10 and decreased the expression of IL-17A. Curcumin attenuates DSS-induced UC injury by regulating Treg/Th17 balance and related cytokine secretion. Thus, curcumin may be a promising therapeutic drug for treating UC.

Human inflammatory disease, multiple sclerosis (MS), is a demyelinating disease of central nervous system (CNS). The experimental autoimmune encephalomyelitis (EAE) is the most commonly used as experimental model because of its key pathological features' approximation of MS. The interaction between complex elements in immune system and in the CNS determines the MS pathogenesis. However, there is no cure for MS and the treatment for MS still encounters great challenges. Thus, finding a more effective disease-modifying treatment is imminent. In the present study, we investigated whether 9,10-Anhydrodehydroartemisin (ADART), a compound derived from artemisinin, could decrease demyelination in EAE and the underlying mechanisms. In established EAE mice, 100 mg/kg 9,10-Anhydrodehydroartemisinin (ADART) effectively reduced CNS and peripheral immune system infiltration inflammatory cells including CD4

Treg/Th17 cell imbalance and inflammatory response may occur in neonatal asthma. IL-35 and BCG have inhibitory effects on inflammatory responses in diseases. However, studies on neonatal asthma after combination of the two have not been reported so far. A respiratory syncytial virus (RSV)-induced neonatal asthma model was first developed in newborn mice. Pathological sections of lung tissue of asthmatic mice were observed by HE staining. Masson staining was used to observe the lung tissue and to compare the deposition of collagen fibers under bronchial epithelium in model mice. The expression of cytokines in serum was detected by ELISA. Giemsa staining analyzed each cell in bronchoalveolar lavage fluid (BALF). Flow cytometry was used to detect the differentiation and development of Treg and Th17 subgroups in BALF. The expression levels of inflammation-related factors were detected by RT-qPCR. Western blot was used to detect the expression of JNK pathway-related proteins. Recombinant IL-35-BCG improved the pathological response of asthmatic mice; inhibited the expression of IgE in serum, neutrophils, macrophages, and eosinophils in BALF; and increased the expression of lymphocytes. In addition, recombinant IL-35-BCG significantly inhibited Th17 differentiation, promoted Treg cell differentiation, and inhibited the expression of inflammatory factors in lung tissue homogenates, thereby reducing allergic airway inflammation. This process might be achieved by inhibiting the JNK signaling pathway. Recombinant IL-35-BCG can regulate Treg/Th17 cell imbalance and inflammatory response in asthmatic newborn mice induced by RSV through JNK signaling pathway, suggesting a new path to neonatal asthma treatment.

Ulcerative colitis (UC) has been considered a Th2- and Th17-related disease. However, anti-IL-12/23 p40 antibody, which blocks Th1 and Th17 cell induction and maintenance, has shown efficacy in treating UC, suggesting that UC might not be a prototypical Th2 and Th17 cell-mediated autoimmune disease. To verify how the immune responses in UC patients interact with each other, we analyzed the cytokine expression and transcription factors involved in the Th1, Th2, and Th17 responses. The mucosal expression of 19 cytokines and transcription factors related to Th1, Th2, and Th17 cells, as well as Tregs, were measured by quantitative polymerase chain reaction using endoscopic biopsy specimens from inflamed colons of UC patients. A correlation analysis between the cytokines and transcription factors was conducted. The characteristic cytokine profile in UC patients has two immune response clusters: Th17-related responses and Th1-/Th2-related responses. IL-23 showed a weaker association with Th17 cell-related cytokines and transcription factor RORC and a much stronger correlation with T-bet and GATA3. In the high-IL-23-expression group, the rate of chronic continuous type was higher and the remission rate lower than in the low-IL-23-expression group. IL-23 may be a very important cytokine for evaluating the UC disease condition, as the expression of IL-23 is associated with certain clinical characteristics of UC patients. A unique association between IL-23 and T-bet/GATA3 might play a key role in the pathogenesis of UC.

Clinical studies have confirmed that the use of antibiotics, especially carbapenems, is a high-risk factor for fungal infection in preterm infants. However, it is not entirely clear whether the increased risk for fungal infection is due to the immune differences in preterm infants or antibiotic usage. We found that after newborn rats received antibiotics, they exhibited significantly impaired anti-Candida albicans immunity in comparison with those without treatment, as shown by significantly increased levels of fungal glucan in the peripheral blood, multiple caseous fungal infections in the abdominal cavity, intestinal congestion, ischemia, and a decrease in the number of intestinal villi. Mechanistically, pretreatment with antibiotics diminished antifungal innate immunity by TLR2 and inhibited IL-17A release and neutrophil recruitment, leading to increased susceptibility to fungi. In summary, we demonstrate that antibiotic usage impairs antifungal immunity in neonates and suggest that antifungal prophylaxis may be required after antibiotic treatment in high-risk preterm babies.

Inflammation is an immune response to exogenous or endogenous insults that helps to maintain the tissue homeostasis under stressful conditions. Depending on the differential types of insults, inflammation is classified into microbial, autoimmune, metabolic, allergic, and physical inflammation. With regard to its involvement in the pathogenesis of most of human diseases, dissecting the key molecules in the regulation of inflammatory process is vital for the prevention and therapeutics of human diseases. Tripartite motif (TRIM) proteins are a versatile family of E3 ligases, which are composed of > 80 distinct members in humans recognized for their roles in antiviral responses. Recently, a large number of studies have shown the regulatory roles of TRIM proteins in mediating the inflammation. Herein in this review, we discuss the aberrations of TRIM proteins in autoimmune and autoinflammatory diseases, with a focus on the regulation of different components of inflammatory process, including inflammasome, NF-κB signaling, type I IFN (interferon) production, and Th1/Th17 cell differentiation. Importantly, elucidation of the mechanism underlying the regulation of inflammation by TRIMs provides insights into the use of TRIMs as therapeutic targets for disease treatment.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high morbidity and mortality. Mesenchymal stem cells (MSCs) have been shown to improve ALI, and the imbalance of regulatory T cells (Tregs) and Th17 cells is associated with mortality in ALI/ARDS patients. However, whether administration of lung-resident MSC (LRMSC) improves lung injury and regulates the balance of Tregs and Th17 cells remains unknown. An ALI animal model was induced by LPS, and PBS or LRMSC were administered via tail vein after 4 h. LRMSC were subsequently detected in the lungs by a live imaging system (Berthold LB983, Germany). Lung morphology; lung wet-to-dry weight ratio; and total protein concentration, inflammatory cells, and cytokines in bronchoalveolar lavage fluid (BALF) and plasma were determined. The percentage of Tregs in lung and spleen, and of Th17 cells in lung and blood, were also evaluated. The results showed that LRMSC not only attenuated histopathological damage but also mediated the downregulation of lung wet-to-dry weight ratio and the reduction of total protein concentration and inflammatory cells in BALF. LRMSC also decreased inflammatory cytokines in both BALF and plasma and increased KGF-2 and surfactant protein C (SPC) expression in the lung. Flow cytometry revealed the upregulation of Tregs and the downregulation of Th17 cells, and the increase in the ratio of Tregs and Th17 cells. The live imaging system showed that LRMSC migrated to and were retained in the injured area. In conclusion, the results indicated that administration of LRMSC attenuates LPS-induced ALI via upregulating the balance of Tregs and Th17 cells.

The cluster of differentiation protein complex, CD80/CD86, regulates Th1/Th2 differentiation in autoimmune disease. In order to establish the effects of CD80/CD86 on Th17 cell differentiation in acute viral myocarditis (VMC), we infected C57BL/6 mice with Coxsackie virus B3 (CVB3) and examined the effects of the treatment with anti-CD80/CD86 monoclonal antibodies (mAbs) on Th17 cell differentiation in vivo. The effects of anti-CD80/CD86 mAbs on Th17 cell differentiation were further evaluated in vitro. The treatment with anti-CD80 mAb induced marked suppression of Th17 cell differentiation and ROR-γt mRNA expression, whereas anti-CD86 mAb alone had no effect, both in vivo and in vitro. Our finding that CD80 regulates Th17 differentiation supports the potential utility of anti-CD80 mAb as an effective new immunotherapeutic target in acute VMC.

Ozone is a strong oxidant in air pollution that exacerbates respiratory disorders and is a major risk factor for acute asthma exacerbation. Ozone can induce reactive oxygen species (ROS) and airway neutrophilic inflammation. In addition, γδT17 cells contribute to IL-17A production upon ozone challenge, resulting in neutrophilic inflammation. It is known, however, that Nrf2 can ameliorate oxidative stress. We therefore investigated whether RTA-408, an Nrf2 activator, can attenuate airway inflammation and inhibit ROS production and whether this effect involves γδT17 cells. Balb/c mice were sensitized/challenged with ovalbumin (OVA) and followed by ozone exposure. We investigated the effect of Nrf2 activator RTA-408 on airway hyperresponsiveness, neutrophilic airway inflammation, cytokine/chemokine production, and OVA-specific IgE level in a mouse model of O3 induced asthma exacerbation. Furthermore, malondialdehyde (MDA) and glutathione (GSH) levels in lung and intracellular ROS were measured. IL-17+ γδT cell percentage by flow cytometer was determined. Nrf2 protein expression by western blot was also examined. We observed that RTA-408 attenuated ROS release during ozone-induced asthma exacerbation and suppressed neutrophil lung infiltration. RTA-408 decreased pro-inflammatory cytokine production and reduced the percentage of IL-17+ γδT cells. Thus, our results suggest that RTA-408 does attenuate airway inflammation in a murine model of ozone-induced asthma exacerbation.

Autotaxin-lysophosphatidic acid (ATX-LPA) axis is closely associated with several inflammation-related diseases. In the colonic mucosa of patients with chronic ulcerative colitis (UC), the expression of ATX and the percentage of Th17 cells are found to increase. However, it is unclear whether ATX-LPA axis affects the differentiation of Th17 cells in chronic UC. To investigate whether ATX-LPA axis contributes to Th17 cell differentiation, a mouse model of chronic UC was established by drinking water with DSS at intervals. ATX inhibitor was used as an intervention. The disease active index (DAI), colonic weight to length ratio, colon length, colon histopathology, and MAdCAM-1 were observed. Additionally, the expression of ATX, LPA receptor, CD34, IL-17A, IL-21, IL-6, ROR-γt, STAT3 in colonic tissue, and the percentage of Th17 cells in spleens and mesenteric lymph nodes (MLNs) were measured using different methods. ATX blockade was able to relieve symptoms and inflammatory response of DSS-induced chronic colitis. The DAI and colonic weight to length ratio were apparently decreased, while the colon length was increased. The pathological damage and colitis severity were lighter in the inhibitor group than that in the DSS group. Inhibiting ATX reduced the expression of ATX, LPA receptor, and CD34 and also decreased the percentages of Th17 cells in spleens and MLNs and the expressions of IL-17A and IL-21, as well as the factors in Th17 cell signaling pathway including IL-6, ROR-γt, and STAT3 in colonic tissue. ATX-LPA axis blockade could alleviate inflammation by suppressing Th17 cell differentiation in chronic UC.

The imbalance of Th17/Treg cells plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Caveolin-1 (Cav-1) has been regarded as a potential critical regulatory protein in pathological mechanisms of chronic inflammatory respiratory diseases. Therefore, we investigated whether the loss of Cav-1 is involved in the homeostasis of Th17/Treg cells in COPD. We examined the expressions of plasma Cav-1 and circulating Th17, Treg cells, and the related cytokines in patients with COPD. Enzyme-linked immunosorbent assay (ELISA) analyses showed a significant reduction of plasma Cav-1 levels in patients with stable COPD (SCOPD) and acutely exacerbated COPD (AECOPD) compared to smokers without COPD. This loss was associated with an increase in frequency of Treg and decreased in frequency of Th17 cells. To further identify the role of Cav-1, we studied the effects of Cav-1 overexpression or downregulation on frequencies of Treg and Th17 cells in peripheral blood mononuclear cells (PBMCs) from subjects. Interestingly, small interfering RNA (siRNA) downregulation of Cav-1 was accompanied by an augmentation of Treg and reduction of Th17 expression. Together, our study demonstrated that the loss of Cav-1 contributed to the imbalance of Th17/Treg cells in patients with COPD.

Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible chronic inflammatory disease associated with the accumulation of activated T cells. To date, there is little information concerning the intrinsic association among Th17, Tc17, and regulatory T (Treg) cells in COPD. The objective of this study was to investigate the variation of lungs CD4(+)Foxp3(+) Treg cells and IL-17-producing CD4 and CD8 (Th17 and Tc17) lymphocytes in mice with cigarette-induced emphysema. Groups of mice were exposed to cigarette smoke or room air. At weeks 12 and 24, mice were sacrificed to observe histological changes by HE stain. The frequencies of Th17 (CD4(+)IL-17(+)T), Tc17 (CD8(+)IL-17(+)T), and Treg (CD4(+)Foxp3(+)T) cells in lungs from these mice were analyzed by flow cytometry. The mRNA levels of orphan nuclear receptor ROR γt and Foxp3 were performed by real-time quantitative polymerase chain reaction. The protein levels of interleukin-17 (IL-17), IL-6, IL-10, and transforming growth factor-beta (TGF-β1) were measured by enzyme-linked immunosorbent assay. Cigarette smoke caused substantial enlargement of the air spaces accompanied by the destruction of the normal alveolar architecture and led to emphysema. The frequencies of Th17 and Tc17 cells, as well as the expressions of IL-6, IL-17, TGF-β1, and ROR γt were greater in the lungs of cigarette smoke (CS)-exposed mice, particularly in the 24-week CS-exposed mice. The frequencies of Treg cells and the expressions of IL-10 and Foxp3 were lower in CS-exposed mice compared to control group. More important, the frequencies of Tregs were negatively correlated with Th17 cells and with Tc17 cells. Interestingly, a significant portion of the cells that infiltrate the lungs was skewed towards a Tc17 phenotype. Our findings suggest the contribution of Th17, Tc17, and Treg cells in the pathogenesis of COPD. Rebalance of these cells will be helpful for developing and refining the new immunological therapies for COPD.

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation and subsequent joint destruction. Previous studies have confirmed that Th17 cells play a critical role in the pathogenesis of RA. MicroRNA (miR)-301a-3p is a regulatory factor for Th17 cells differentiation that contributes to the pathogenesis of autoimmune diseases. The purposes of this study were to identify the alteration of Th17 cells and analyze the correlation between the expression of the miR-301a-3p and the proportion of Th17 cells in RA patients. The results showed that the frequency of Th17 cells and the expression of transcription factors (RORγt and STAT3) significantly increased in the peripheral blood mononuclear cells (PBMCs) from RA patients, and the associated proinflammatory cytokines were also upregulated. We also observed that the expression of protein inhibitor of activated STAT3 (PIAS3), the main cellular inhibitor of STAT3, was attenuated in RA patients and negatively correlated with the percentage of Th17 cells in RA. Interestingly, miR-301a-3p, an inhibitor of PIAS3 expression, was overexpressed in the PBMCs from RA patients and positively correlated with the frequency of Th17 cells in patients with RA. Taken together, these data indicated that miR-301a-3p and Th17 cells were augmented in peripheral blood, which may play an important role in the process of RA.

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Acute gouty arthritis is the inflammation of joint tissues in the acute form due to the deposition of monosodium urate (MSU) crystals. Regulatory T cells (Tregs) and Th17 cells play an important role in the development and progression of inflammatory diseases. However, the expression and role of Tregs and Th17 cells are not clear in this disease. Here, we investigated the changes of Tregs, Th17 cells, and Treg/Th17 ratio in spleen, as well as the inflammatory cytokines in blood and joint tissue pathology in acute gouty arthritis rat induced by MSU. We found that both the percentages of Tregs and Th17 cells in spleen increased at an early stage (6 h). Tregs decreased at 12 and 24 h, and rise again at 48 and 72 h. However, Th17 cells reached its peak at 24 h, and then decreased after 48 h. Treg/Th17 ratio showed an initial decrease and then increase, and further reached its minimum value at 24 h. But the ratios of Treg/Th17at all times were lower than that of normal control. The level of serum cytokines (IL-1β, IL-6, IL-17, TNF-α, and IL-10) showed an opposite trend to Treg/Th17 ratio, except the level of TGF-β1 was similar to Tregs. In summary, Tregs and Th17 cells in spleen changed over time during the development of acute gouty arthritis. Decrease of Treg/Th17 ratio was consistent with inflammation development in the joints, suggesting that Treg/Th17 imbalance may involve in pathogenesis of acute gouty arthritis.

Periodontitis is a dysbiotic bacteria-mediated disease characterized by periodontal inflammations and alveolar bone damage. Its mechanisms were complicated, involving an inflammation-mediated bone destruction. We sought to determine roles and rules that CD8

Recently, FGF21 was reported to play an important role in anti-inflammation. The aim of the study is to explore the mechanism for FGF21 alleviating inflammation of CIA. CIA mice were injected with FGF21 once a day for 28 days after first booster immunization. The results showed that FGF21 alleviates arthritis severity and decreases serum anti-CII antibodies levels in CIA mice. Compared with CIA model, the number of the splenic TH17 cells was significantly decreased in FGF21-treated mice. FGF21 treatment reduced the mRNA expression of IL-17, TNF-α, IL-1β, IL-6, IL-8, and MMP3 and increased level of IL-10 in the spleen tissue. The expression of STAT3 and phosphorylated STAT3 was suppressed in FGF21-treated group. The mRNA expression of RORγt and IL-23 also decreased. In conclusion, these findings suggest that the beneficial effects of FGF21 on CIA mice were achieved by down-regulating Th17-IL-17 axis through STAT3/RORγt pathway. Modulating of Th17-mediated inflammatory response may be one of the mechanisms for FGF21 attenuating inflammation in CIA.

Citrate is commonly used as an anticoagulant in hemodialysis for chronic renal failure (CRF) and for the regulation of the immune dysfunction in CRF patients. The objective of this study was to investigate the effect of citrate on the balance of T helper 17 (Th17) and regulatory T (Treg) cells in CRF. The levels of blood urea nitrogen (BUN) and serum creatinine (Scr) were significantly increased in the CRF model group compared to the control group, and were decreased in the citrate-treated groups. Citrate treatment inhibited the viability of Th17 cells while elevating the viability of Treg cells in CRF rats. Moreover, Th17-related cytokines significantly decreased while the Treg-related cytokines significantly increased with citrate treatment. Moreover, citrate had a negative influence on the deviation of Th17/Treg cells in CRF rats. Therefore, our study suggests that citrate had an anti-inflammatory effect on CRF through the modulation of the Th17/Treg balance.

T helper 17 (Th17) cells play an important role in allergic asthma, and the Notch ligand Delta-like ligand (Dll)4 has been reported to direct the differentiation of Th17 cells. In this study, experimental animals were divided into five groups (control group, asthma group, physiological saline group, anti-Dll4 antibody group, and immunoglobulin G group). The study aimed to explore the effect of anti-Dll4 antibody on the differentiation of Th17 cell in asthmatic mice. Dll4 protein expressions were performed by immunohistochemical imaging. The proportion of Th17 cells in mouse spleen-isolated CD4+ T cells were measured by flow cytometry. The protein expression of Th17 transcription factor retinoid-related orphan nuclear receptor (RORγt) was detected by Western blotting. Interleukin (IL)-17 levels in serum were measured by enzyme-linked immunosorbent assay (ELISA). The study found that the expression of Dll4 in lung tissue from the asthma group significantly increased compared with the anti-Dll4 antibody group. The ratio of Th17 cells in CD4+ T cells was significantly downregulated, and the protein expression of RORγt in spleen significantly reduced in the anti-Dll4 antibody group compared with the asthma group. Moreover, the IL-17 level in serum from the anti-Dll4 antibody group significantly reduced compared with the asthma group. These results suggested that anti-Dll4 antibody could inhibit the differentiation of Th17 cells in asthmatic mice.

The aim of the current study was to use a mouse model of allergic asthma to investigate whether cordycepin has antiasthmatic effects, and if so, to determine the mechanism of these effects. A total of 50 mice were randomly assigned to five experimental groups: control, model, dexamethasone (Dex, 2 mg/kg), and cordycepin (20-40 mg/kg). Histological studies were evaluated by the hematoxylin and eosin staining, OVA-specific serum and BALF IgE levels and Treg/Th17 cytokines were evaluated by enzyme-linked immunosorbent assay, and RORγt and Foxp3 were evaluated by western blot. Our study demonstrated that cordycepin inhibited OVA-induced increases in eosinophil count; IL-17A levels were recovered and increased IL-10 levels in bronchoalveolar lavage fluid. Histological studies demonstrated that cordycepin substantially inhibited OVA-induced eosinophilia in lung tissue. Western blot study demonstrated that cordycepin increased Foxp3 and inhibited RORγt. These findings suggest that cordycepin may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma.

Being a member of the early growth response (Egr) family of transcription factors, Egr-2 is expressed in a variety of cell types of the immune system. Recent findings imply that Egr-2 is important in the development and function of T helper (Th) 17 cell, regulatory T (Treg) cell, as well as dendritic cell (DC). Although these cells perform significantly in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and systemic sclerosis, the roles of Egr-2 in the pathogenesis of autoimmune diseases can not be neglected. In this article, we will discuss recent findings about the important roles of Egr-2 in immune cells and the possible pathological roles of Egr-2 in autoimmune diseases.

Immunological responses to pathogens are stringently regulated in the eye to prevent excessive inflammation that damage ocular tissues and compromise vision. Suppressors of cytokine signaling (SOCS) regulate intensity/duration of inflammatory responses. We have used SOCS1-deficient mice and retina-specific SOCS1 transgenic rats to investigate roles of SOCS1 in ocular herpes simplex virus (HSV-1) infection and non-infectious uveitis. We also genetically engineered cell-penetrating SOCS proteins (membrane-translocating sequence (MTS)-SOCS1, MTS-SOCS3) and examined whether they can be used to inhibit inflammatory cytokines. Overexpression of SOCS1 in transgenic rat eyes attenuated ocular HSV-1 infection while SOCS1-deficient mice developed severe non-infectious anterior uveitis, suggesting that SOCS1 may contribute to mechanism of ocular immune privilege by regulating trafficking of inflammatory cells into ocular tissues. Furthermore, MTS-SOCS1 inhibited IFN-γ-induced signal transducers and activators of transcription 1 (STAT1) activation by macrophages while MTS-SOCS3 suppressed expansion of pathogenic Th17 cells that mediate uveitis, indicating that MTS-SOCS proteins maybe used to treat ocular inflammatory diseases of infectious or autoimmune etiology.