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Giusy Daniela Albano Caterina Di Sano Anna Bonanno Loredana Riccobono Rosalia Gagliardo Pascal Chanez Mark Gjomarkaj Angela Marina Montalbano Giulia Anzalone Stefania La Grutta Fabio Luigi Massimo Ricciardolo Mirella Profita 《PloS one》2013,8(4)
Th17 cells and IL-17A play a role in the development and progression of allergic diseases. We analyzed the IL-17A levels in sputum supernatants (Ss), nasal wash (NW) and plasma (P) from Healthy Controls (HC) and children with Asthma/Rhinitis. We tested the expression of IL-17A, RORγ(t) and FOXP3 in peripheral blood T-lymphocytes from intermittent and mild-moderate asthma. The effect of Budesonide and Formoterol was tested “in vitro” on IL-17A, RORγ(t) and FOXP3 expression in cultured T-lymphocytes from mild-moderate asthma/persistent rhinitis patients, and on nasal and bronchial epithelial cells stimulated with NW and Ss from mild-moderate asthma/persistent rhinitis. Further, the effect of 12 weeks of treatment with Budesonide and Formoterol was tested “in vivo” in T-lymphocytes from mild-moderate asthma/persistent rhinitis patients. IL-17A was increased in Ss, NW and P from children with mild-moderate asthma compared with intermittent and HC. In cultured T-lymphocytes IL-17A and RORγ(t) expression were higher in mild-moderate asthma/persistent rhinitis than in mild-moderate asthma/intermittent rhinitis, while FOXP3 was reduced. Budesonide with Formoterol reduced IL-17A and RORγ(t), while increased FOXP3 in cultured T-lymphocytes from mild-moderate asthma/persistent rhinitis, and reduced the IL-8 release mediated by IL-17A present in NW and Ss from mild-moderate asthma/persistent rhinitis in nasal and bronchial epithelial cells. Finally, Budesonide with Formoterol reduced IL-17A levels in P and Ss, CD4+IL-17A+T-cells, in naïve children with mild-moderate asthma/persistent rhinitis after 12 weeks of treatment. Th17 mediated immunity may be involved in the airway disease of children with allergic asthma and allergic rhinitis. Budesonide with Formoterol might be a useful tool for its therapeutic control. 相似文献
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Tej Pratap Singh Augusto M. Carvalho Laís Amorim Sacramento Elizabeth A. Grice Phillip Scott 《PLoS pathogens》2021,17(10)
Innate lymphoid cells (ILCs) comprise a heterogeneous population of immune cells that maintain barrier function and can initiate a protective or pathological immune response upon infection. Here we show the involvement of IL-17A-producing ILCs in microbiota-driven immunopathology in cutaneous leishmaniasis. IL-17A-producing ILCs were RORγt+ and were enriched in Leishmania major infected skin, and topical colonization with Staphylococcus epidermidis before L. major infection exacerbated the skin inflammatory responses and IL-17A-producing RORγt+ ILC accumulation without impacting type 1 immune responses. IL-17A responses in ILCs were directed by Batf3 dependent CD103+ dendritic cells and IL-23. Moreover, experiments using Rag1-/- mice established that IL-17A+ ILCs were sufficient in driving the inflammatory responses as depletion of ILCs or neutralization of IL-17A diminished the microbiota mediated immunopathology. Taken together, this study indicates that the skin microbiota promotes RORγt+ IL-17A-producing ILCs, which augment the skin inflammation in cutaneous leishmaniasis. 相似文献
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Th17 cells have been reported to produce proinflammatory cytokines like Interleukin-17, IL-22, and regarded as important players in various inflammatory diseases. One of the IL-12 cytokine family cytokines, IL-23, composed of p19 and p40 subunit, is known for its potential to promote Th17 development and IL-17 producing, and the IL-23/IL-17 pathway is considered to be potential therapeutic target for autoimmune inflammation responses. Knockout mice deficient in either IL-23 or IL-17 related genes can suppress the allergic responses. Several IL-23 or IL-17 neutralizing agents are being evaluated in vitro or in vivo to disrupt the IL-23/IL-17 axis. Herein, we report that prokaryotically expressed soluble IL-23 receptor cytokine-binding homology region as an endogenous extracellular receptor analogue could be a natural antagonist against IL-23/IL-17 axis. We provide evidence that IL23R-CHR can bind to IL-23 in a dose-dependent manner in vitro, and block IL-23 signal by IL23R-CHR reducing the RORγt expression, which in turn lowers the expression of IL-17/IL-22, thus protecting naive CD4+ T cells against Th17 development. Together, this study indicates the importance of IL-23 pathway in Th17 development and the negative regulation of Th17 development by IL23R-CHR, and highlights the important roles of the soluble receptor extracellular region in the therapeutic strategy of neutralizing IL-23. 相似文献
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Gasse P Riteau N Vacher R Michel ML Fautrel A di Padova F Fick L Charron S Lagente V Eberl G Le Bert M Quesniaux VF Huaux F Leite-de-Moraes M Ryffel B Couillin I 《PloS one》2011,6(8):e23185
Background
Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice.Methods
The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice.Results
We show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt+ γδ T cells and to a lesser extent by CD4αβ+ T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis.Conclusions
Our findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology. 相似文献6.
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Mariángeles Noto Llana Sebastián Hernán Sarnacki María del Rosario Aya Casta?eda María Isabel Bernal Mónica Nancy Giacomodonato María Cristina Cerquetti 《PloS one》2013,8(12)
Reactive arthritis is the development of sterile joint inflammation as a sequel to a remote infection, often in the gut. We have previously shown that a low dose of S. enteritidis inoculated to streptomycin-pretreated mice generates a self-limiting enterocolitis suitable for studying reactive arthritis. Here we show that consumption of Lactobacillus casei prior to infection abolishes intestinal and joint inflammation triggered by Salmonella. BALB/c mice were sacrificed after infection; intestinal and joint samples were analyzed for histological changes and expression of cytokines. TNF-α was measured by ELISA and the expression of IL-1β, IL-6, IL-10, IL-17, IL-23 and TGF-β was assessed by qPCR. L. casei consumption prevented Salmonella-induced synovitis, the increment of TNF-α in knees and the increase of IL-17 expression in popliteal and inguinal lymph nodes. At intestinal level consumption of L. casei drastically diminished S. enteritidis invasiveness and shortened splenic persistence of the pathogen. Bacterial loads recovered at days 2 and 5 from Peyer’s patches were 10-fold lower in mice fed with L. casei. In accordance, we found that the augment in gut permeability induced during enterocolitis was decreased in those animals. Consumption of L. casei prior to infection failed to increase anti- inflammatory molecules such as IL-10 and TGF-β in the intestine. On the other hand, consumption of L. casei abrogated the expression of TNF-α, IL-17, IL-23, IL-1β and IL-6 in cecum and mesenteric lymph nodes. These cytokines are needed for differentiation of immune cells involved in the development of reactive arthritis such as Th17 and γδ T cells. Trafficking of these inflammatory cells from the gut to the joints has been proposed as a mechanism of generation of reactive arthritis. Our results suggest that L. casei consumption prevents Salmonella-induced synovitis by altering the intestinal milieu necessary for differentiation of cells involved in the generation of joint inflammation. 相似文献
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Atsuhiro Matsumoto Takanori Kanai Yohei Mikami Po–Sung Chu Nobuhiro Nakamoto Hirotoshi Ebinuma Hidetsugu Saito Toshiro Sato Hideo Yagita Toshifumi Hibi 《PloS one》2013,8(4)
Retinoid-related orphan receptor (ROR) γt is known to be related to the development and function of various immunological compartments in the liver, such as Th17 cells, natural killer T (NKT) cells, and innate lymphoid cells (ILCs). We evaluated the roles of RORγt-expressing cells in mouse acute hepatitis model using RORγt deficient (RORγt−/−) mice and RAG-2 and RORγt double deficient (RAG-2−/− × RORγt−/−) mice. Acute hepatitis was induced in mice by injection with carbon tetrachloride (CCl4), to investigate the regulation of liver inflammation by RORγt-expressing cells. We detected RORC expression in three compartments, CD4+ T cells, NKT cells, and lineage marker-negative SCA-1+Thy1high ILCs, of the liver of wild type (WT) mice. CCl4-treated RORγt−/− mice developed liver damage in spite of lack of RORγt-dependent cells, but with reduced infiltration of macrophages compared with WT mice. In this regard, ILCs were significantly decreased in RAG-2−/− × RORγt−/− mice that lacked T and NKT cells. Surprisingly, RAG-2−/− × RORγt−/− mice developed significantly severer CCl4-induced hepatitis compared with RAG-2−/− mice, in accordance with the fact that hepatic ILCs failed to produce IL-22. Lastly, anti-Thy1 monoclonal antibody (mAb), but not anti-NK1.1 mAb or anti-asialo GM1 Ab administration exacerbated liver damage in RAG-2−/− mice with the depletion of liver ILCs. Collectively, hepatic RORγt-dependent ILCs play a part of protective roles in hepatic immune response in mice. 相似文献
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IL-17-producing CD4+ T helper 17 (Th17) cells are pathogenic in a range of human autoimmune diseases and corresponding animal models. We now demonstrate that such T cells infiltrating the target organ during the induction of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveoretinitis (EAU) specifically express NR4A2. Further, we reveal a critical involvement of NR4A2 in Th17 cell functions and Th17 cell-driven autoimmune diseases. When NR4A2 expression was blocked with siRNA, full Th17 differentiation was prevented in vitro: although cells expressed the master Th17 regulator, RORγt, they expressed reduced levels of IL-23R and were unable to produce IL-17 and IL-21. Notably, Th17 differentiation in the absence of NR4A2 was restored by exogenous IL-21, indicating that NR4A2 controls full maturation of Th17 cells via autocrine IL-21 signalling. Preventing NR4A2 expression in vivo by systemic treatment with NR4A2-specific siRNA also reduced Th17 effector responses and furthermore protected mice from EAE induction. In addition, the lack of disease was associated with a reduction in autocrine IL-21 production and IL-23R expression. Similar modulation of NR4A2 expression was also effective as an intervention, reversing established autoimmune responses and ameliorating clinical disease symptoms. Thus, NR4A2 appears to control Th17 differentiation and so plays an essential role in the development of Th17-mediated autoimmune disease. As NR4A2 is also upregulated during human autoimmune disease, targeting NR4A2 may provide a new therapeutic approach in treating autoimmune disease. 相似文献
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Alayna K. Caffrey Margaret M. Lehmann Julianne M. Zickovich Vanessa Espinosa Kelly M. Shepardson Christopher P. Watschke Kimberly M. Hilmer Arsa Thammahong Bridget M. Barker Amariliz Rivera Robert A. Cramer Joshua J. Obar 《PLoS pathogens》2015,11(1)
Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how A. fumigatus growth is controlled in the respiratory tract is developing, but still limited. Alveolar macrophages, lung resident macrophages, and airway epithelial cells constitute the first lines of defense against inhaled A. fumigatus conidia. Subsequently, neutrophils and inflammatory CCR2+ monocytes are recruited to the respiratory tract to prevent fungal growth. However, the mechanism of neutrophil and macrophage recruitment to the respiratory tract after A. fumigatus exposure remains an area of ongoing investigation. Here we show that A. fumigatus pulmonary challenge induces expression of the inflammasome-dependent cytokines IL-1β and IL-18 within the first 12 hours, while IL-1α expression continually increases over at least the first 48 hours. Strikingly, Il1r1-deficient mice are highly susceptible to pulmonary A. fumigatus challenge exemplified by robust fungal proliferation in the lung parenchyma. Enhanced susceptibility of Il1r1-deficient mice correlated with defects in leukocyte recruitment and anti-fungal activity. Importantly, IL-1α rather than IL-1β was crucial for optimal leukocyte recruitment. IL-1α signaling enhanced the production of CXCL1. Moreover, CCR2+ monocytes are required for optimal early IL-1α and CXCL1 expression in the lungs, as selective depletion of these cells resulted in their diminished expression, which in turn regulated the early accumulation of neutrophils in the lung after A. fumigatus challenge. Enhancement of pulmonary neutrophil recruitment and anti-fungal activity by CXCL1 treatment could limit fungal growth in the absence of IL-1α signaling. In contrast to the role of IL-1α in neutrophil recruitment, the inflammasome and IL-1β were only essential for optimal activation of anti-fungal activity of macrophages. As such, Pycard-deficient mice are mildly susceptible to A. fumigatus infection. Taken together, our data reveal central, non-redundant roles for IL-1α and IL-1β in controlling A. fumigatus infection in the murine lung. 相似文献
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Tongzhou Liang Taiqiu Chen Jincheng Qiu Wenjie Gao Xianjian Qiu Yuanxin Zhu Xudong Wang Yanbo Chen Hang Zhou Zhihuai Deng Pengfei Li Caixia Xu Yan Peng Anjing Liang Peiqiang Su Bo Gao Dongsheng Huang 《Cell death & disease》2021,12(10)
Osteoarthritis (OA) is characterized by cartilage destruction, chronic inflammation, and local pain. Evidence showed that retinoic acid receptor-related orphan receptor-α (RORα) is crucial in cartilage development and OA pathogenesis. Here, we investigated the role and molecular mechanism of RORα, an important member of the nuclear receptor family, in regulating the development of OA pathologic features. Investigation into clinical cartilage specimens showed that RORα expression level is positively correlated with the severity of OA and cartilage damage. In an in vivo OA model induced by anterior crucial ligament transaction, intra-articular injection of si-Rora adenovirus reversed the cartilage damage. The expression of cartilage matrix components type II collagen and aggrecan were elevated upon RORα blockade. RNA-seq data suggested that the IL-6/STAT3 pathway is significantly downregulated, manifesting the reduced expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, including interaction with STAT3 and IL-6 promoter. Taken together, our findings indicated the pivotal role of the RORα/IL-6/STAT3 axis in OA progression and confirmed that RORα blockade improved the matrix catabolism in OA chondrocytes. These results may provide a potential treatment target in OA therapy.Subject terms: Nuclear receptors, Osteoarthritis 相似文献
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Shuhei Kobayashi Akira Hara Takayuki Isagawa Ichiro Manabe Kiyoshi Takeda Takashi MaruYama 《PloS one》2014,9(10)
The nuclear IκB family protein IκBNS is expressed in T cells and plays an important role in Interferon (IFN)-γ and Interleukin (IL)-2 production. IκB-ζ, the most similar homolog of IκBNS, plays an important role in the generation of T helper (Th)17 cells in cooperation with RORγt, a master regulator of Th17 cells. Thus, IκB-ζ deficient mice are resistant to Th17-dependent experimental autoimmune encephalomyelitis (EAE). However, IκB-ζ deficient mice develop the autoimmune-like Sjögren syndrome with aging. Here we found that IκBNS-deficient (Nfkbid−/−) mice show resistance against developing Th17-dependent EAE. We found that Nfkbid−/− T cells have decreased expression of IL-17-related genes and RORγt in response to Transforming Growth Factor (TGF)-β1 and IL-6 stimulation. Thus, IκBNS plays a pivotal role in the generation of Th17 cells and in the control of Th17-dependent EAE. 相似文献
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Amélie Savers Orhan Rasid Marianna Parlato Matthias Brock Gregory Jouvion Bernhard Ryffel Jean-Marc Cavaillon Gerard Eberl Ouma?ma Ibrahim-Granet 《PloS one》2016,11(4)
Phagocytes restrict the germination of Aspergillus fumigatus conidia and prevent the establishment of invasive pulmonary aspergillosis in immunecompetent mice. Here we report that immunecompetent mice recovering from a primary A. fumigatus challenge are protected against a secondary lethal challenge. Using RAGγc knock-out mice we show that this protection is independent of T, B and NK cells. In protected mice, lung phagocytes are recruited more rapidly and are more efficient in conidial phagocytosis and killing. Protection was also associated with an enhanced expression of CXCR2 and Dectin-1 on bone marrow phagocytes. We also show that protective lung cytokine and chemokine responses are induced more rapidly and with enhanced dynamics in protected mice. Our findings support the hypothesis that following a first encounter with a non-lethal dose of A. fumigatus conidia, the innate immune system is primed and can mediate protection against a secondary lethal infection. 相似文献
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Jacqueline Georgy Yvonne Arlt Jens M. Moll Meryem Ouzin Hendrik T. Weitz Lothar Gremer Dieter Willbold Joachim Grtzinger Felix Thives-Kurenbach Jürgen Scheller Doreen M. Floss 《The Journal of biological chemistry》2021,297(5)
Interleukin (IL)-12 and IL-23 are composite cytokines consisting of p35/p40 and p19/p40, respectively, which signal via the common IL-12 receptor β1 (IL-12Rβ1) and the cytokine-specific receptors IL-12Rβ2 and IL-23R. Previous data showed that the p40 component interacts with IL-12Rβ1, whereas p19 and p35 subunits solely bind to IL-23R and IL-12Rβ2, resulting in tetrameric signaling complexes. In the absence of p19 and p35, p40 forms homodimers and may induce signaling via IL-12Rβ1 homodimers. The critical amino acids of p19 and p35 required for binding to IL-23R and IL-12Rβ2 are known, and two regions of p40 critical for binding to IL-12Rβ1 have recently been identified. In order to characterize the involvement of the N-terminal region of p40 in binding to IL-12Rβ1, we generated deletion variants of the p40-p19 fusion cytokine. We found that an N-terminal deletion variant missing amino acids M23 to P39 failed to induce IL-23-dependent signaling and did not bind to IL-12Rβ1, whereas binding to IL-23R was maintained. Amino acid replacements showed that p40W37K largely abolished IL-23-induced signal transduction and binding to IL-12Rβ1, but not binding to IL-23R. Combining p40W37K with D36K and T38K mutations eliminated the biological activity of IL-23. Finally, homodimeric p40D36K/W37K/T38K did not interact with IL-12Rβ1, indicating binding of homodimeric p40 to IL-12Rβ1 is comparable to the interaction of IL-23/IL-12 and IL-12Rβ1. In summary, we have defined D36, W37, and T38 as hotspot amino acids for the interaction of IL-12/IL-23 p40 with IL-12Rβ1. Structural insights into cytokine–cytokine receptor binding are important to develop novel therapeutic strategies. 相似文献
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Jun Young Hong Yutein Chung Jessica Steenrod Qiang Chen Jing Lei Adam T Comstock Adam M Goldsmith J Kelley Bentley Uma S Sajjan Marc B Hershenson 《Respiratory research》2014,15(1):63