Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells
Open accessAbstract
Cognate antigen recognition by CD4+ T cells is thought to contribute to the tissue specificity of various autoimmune diseases, particularly those associated with class II MHC alleles. However, we show that localized class II MHC–dependent arthritis in F759 mice depends on local events that result in the accumulation of activated CD4+ T cells in the absence of cognate antigen recognition. In this model, transfer of in vitro polarized Th17 cells combined with the induction of experimental microbleeding resulted in CCL20 production, the accumulation of T cells in the joints, and local production of IL-6. Disease induction required IL-17A production by transferred T cells, IL-6 and CCL20 expression, and STAT3 signaling in type I collagen–expressing cells. Our data suggest a model in which the development of autoimmune disease in F759 mice depends on four events: CD4+ T cell activation regardless of antigen specificity, local events that induce T cell accumulation, enhanced sensitivity to T cell–derived cytokines in the tissue, and activation of IL-6 signaling in the tissue. This model provides a possible explanation for why tissue-specific antigens recognized by activated CD4+ T cells have not been identified in many autoimmune diseases, especially those associated with class II MHC molecules.
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Disease induction requires IL-17A production by transferred T cells, IL-6 and CCL20 expression and STAT3 signaling in type I collagen-expressing cells.
“The disease induction requires IL-17A production by transferred T cells, IL-6 and CCL20 expression and STAT3 signaling in type I collagen-expressing cells.”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [52]
The Results report that IL-6-deficient mice and mice lacking STAT3 in type I collagen-expressing cells did not develop arthritis, and that joint CCL20 knockdown prevented arthritis after Th17 transfer and microbleeding. But the Results also report mild arthritis after transfer of IL-17A-deficient Th17 cells. IL-17A therefore contributes to disease induction but is not strictly required as the claim states. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTissue property-dependent events, microbleeding, neural stimulation, cell senescence and oncogenic mutations in pre-neoplastic cells have been shown to trigger interactions between immune cells and non-immune tissues.
“Furthermore, tissue property-dependent events (49), microbleeding (52, 53), neural stimulation (54, 55), cell senescence (56, 57) and oncogenic mutations in pre-neoplastic cells have been shown to trigger these interactions.”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [52]
Even T-cell-dependent tissue-specific autoimmune diseases do not necessarily require antigen-specific T cells.
“These results suggest even T-cell-dependent tissue-specific autoimmune diseases do not necessarily require antigen-specific T cells (52).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [52]
Local initiators such as microbleeding induce the accumulation of T cells in the joints through CCL20 production.
“Murakami et al. demonstrated that local initiators such as microbleeding induce the accumulation of T cells in the joints through CCL20 production (52).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [52]
F759 mice bred by mating T-cell antigen-receptor transgenic mice and Rag2-KO mice to express only one T-cell antigen-receptor on CD4(+) T cells still develop arthritis.
“F759 mice bred by mating T-cell antigen-receptor transgenic mice and Rag2-KO mice to express only one T-cell antigen-receptor on CD4(+) T cells still develop arthritis.”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [52]
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“Consistent with this, jointspecific antigenic peptides have been identified in humans (derivatives of aggrecan, fibrillin, collagen, etc.; Polgár et al., 2003; Chapuy-Regaud et al., 2005; Elsaid and Chichester, 2006; Takizawa et al., 2006; Van Steendam et al., 2010).”
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“Consistent with this, jointspecific antigenic peptides have been identified in humans (derivatives of aggrecan, fibrillin, collagen, etc.; Polgár et al., 2003; Chapuy-Regaud et al., 2005; Elsaid and Chichester, 2006; Takizawa et al., 2006; Van Steendam et al., 2010).”
Review: Collagen markers in early arthritic diseases.
Elsaid, K., & Chichester, C. (2006) · Clinica chimica acta; international journal of clinical chemistry · doi:10.1016/j.cca.2005.09.020 · Cited by 92 · cited 1× · see citing works
“Consistent with this, jointspecific antigenic peptides have been identified in humans (derivatives of aggrecan, fibrillin, collagen, etc.; Polgár et al., 2003; Chapuy-Regaud et al., 2005; Elsaid and Chichester, 2006; Takizawa et al., 2006; Van Steendam et al., 2010).”
Hakobyan, N., Enockson, C., Cole, A. A., Sumner, D. R., & Valentino, L. (2008) · Haemophilia · doi:10.1111/j.1365-2516.2008.01689.x · Cited by 91 · cited 2× · see citing works
“It is known that microbleeding, which occurs even in the joints of healthy individuals, can trigger hemarthrosis in hemophilia patients because of defects in blood coagulation (Aledort et al., 1994; Manco-Johnson et al., 2007; Hakobyan et al., 2008).”
Immune receptor signaling, aging, and autoimmunity
Hasler, P., & Zouali, M. (2005) · Cellular Immunology · doi:10.1016/j.cellimm.2005.04.012 · Cited by 84 · cited 1× · see citing works
“Consistent with this, these diseases are more prevalent in older patients who have a large population of memory/activated CD4+ T cells, some of which secrete cytokines because of homeostatic proliferation and/or chronic inflammations (Hasler and Zouali, 2005; Larbi et al., 2008).”
Khiong, K., Murakami, M., Kitabayashi, C., Ueda, N., Sawa, S.-I., Sakamoto, A., Kotzin, B., Rozzo, S., Ishihara, K., Verella-Garcia, M., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30513 · Cited by 82 · cited 2× · see citing works
“…with a specific cytokine profile that includes IL-17A and IFN- from homeostatic proliferating CD4+ T cells (Gudmundsdottir and Turka, 2001; Khiong et al., 2007; Nishihara et al., 2007). circles in a; n = 47, 47, 40, 37, 31, 20, 10, and 6 for 1, 2, 3, 4, 5, 6, 7, and 8 mo, respectively),…”
Self-citationIL-6 positively regulates Foxp3+CD8+ T cells in vivo.
Nakagawa, T., Tsuruoka, M., Ogura, H., Okuyama, Y., Arima, Y., Hirano, T., & Murakami, M. (2010) · International Immunology · doi:10.1093/intimm/dxp119 · Cited by 69 · cited 2× · see citing works
“…we have previously shown that MHC II–restricted CD4+ T cells, but not CD8+ T cells and B cells, enhance the development of arthritis in F759 mice (Sawa et al., 2006), whereas a subset of CD8+ T cells expressing Foxp3 negatively regulates arthritis development in these mice (Nakagawa et al., 2010).”
Self-citationTwo Types of Mouse Helper T Cell Clone: Differences in B Cell Help and Lymphokine Synthesis
Mosmann, T., Cherwinski, H., Cher, D., & Coffman, R. (1987) · doi:10.1007/978-1-4612-4598-8_14 · Cited by 65 · cited 4×
“Furthermore, activated CD4+ T cells are known to express TNF (Cherwinski et al., 1987; Constant and Bottomly, 1997; Williams et al., 2008), whereas we have found that a lack of TNF attenuates arthritis in F759 mice (unpublished data).”
InfluentialMaffia, P., Brewer, J., Gracie, J., Ianaro, A., Leung, B. F., Mitchell, P., Smith, K., McInnes, I., & Garside, P. (2004) · Journal of Immunology · doi:10.4049/jimmunol.173.1.151 · Cited by 62 · see citing works
Polgár, A., Falus, A., Koó, É., Újfalussy, I., Seszták, M., Szûts, I., Konrád, K., Hodinka, L., Bene, E., Mészáros, G., et al. (2003) · Rheumatology · doi:10.1093/rheumatology/keg168 · Cited by 57 · cited 1× · see citing works
“Consistent with this, jointspecific antigenic peptides have been identified in humans (derivatives of aggrecan, fibrillin, collagen, etc.; Polgár et al., 2003; Chapuy-Regaud et al., 2005; Elsaid and Chichester, 2006; Takizawa et al., 2006; Van Steendam et al., 2010).”
Animal models of arthritis caused by systemic alteration of the immune system.
Sakaguchi, S., & Sakaguchi, N. (2005) · Current Opinion in Immunology · doi:10.1016/j.coi.2005.09.017 · Cited by 43 · cited 1× · see citing works
“Of special interest is IL-6, which several studies have suggested has an important role in autoimmune diseases (Hirano, 1998, 2010; O’Shea et al., 2002; Sakaguchi and Sakaguchi, 2005; Awasthi and Kuchroo, 2009).”
Epstein-Barr virus-derived EBNA2 regulates STAT3 activation
Muromoto, R., Ikeda, O., Okabe, K., Togi, S., Kamitani, S., Fujimuro, M., Harada, S., Oritani, K., & Matsuda, T. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.11.053 · Cited by 42 · cited 1× · see citing works
“Moreover, many viral proteins, including hepatitis C virus Core protein and EBNA2 from Epstein-Barr virus, are strong STAT3 activators (Yoshida et al., 2002; Muromoto et al., 2009).”
Jang, E., Kim, H. R., Cho, S.-H., Paik, D., Kim, J., Lee, S.-K., & Youn, J. (2006) · Arthritis & Rheumatism · doi:10.1002/art.21567 · Cited by 42 · cited 1× · see citing works
“Furthermore, we and others have shown that homeostatic proliferation of CD4+ T cells is involved in the development of diabetes, arthritis, and Omenn syndrome (King et al., 2004; Jang et al., 2006; Sawa et al., 2006; Khiong et al., 2007).”
Immune receptor signaling, aging and autoimmunity.
Larbi, A., Fülöp, T., & Pawelec, G. (2008) · Advances in Experimental Medicine and Biology · doi:10.1007/978-0-387-09789-3_21 · Cited by 37 · cited 1× · see citing works
“Consistent with this, these diseases are more prevalent in older patients who have a large population of memory/activated CD4+ T cells, some of which secrete cytokines because of homeostatic proliferation and/or chronic inflammations (Hasler and Zouali, 2005; Larbi et al., 2008).”
Nickdel, M. B., Conigliaro, P., Valesini, G., Hutchison, S., Benson, R., Bundick, R., Leishman, A., McInnes, I., Brewer, J. M., & Garside, P. (2008) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.089300 · Cited by 35 · cited 1× · see citing works
“Moreover, it is interesting that LPS administration around the joints induces arthritis in mice that have an excess number of Th1 cells (Nickdel et al., 2009).”
Targeting lymphocyte activation to treat rheumatoid arthritis.
Falgarone, G., Semerano, L., Rullé, S., & Boissier, M. (2009) · Joint, bone, spine : revue du rhumatisme · doi:10.1016/j.jbspin.2008.12.007 · Cited by 27 · cited 1× · see citing works
“RA and arthritis in F759 mice are such examples (Falgarone et al., 2009; this paper).”
The role of autoantigens in autoimmune disease.
Mocci, S., Lafferty, K. J., & Howard, M. C. (2000) · Current Opinion in Immunology · doi:10.1016/s0952-7915(00)00169-2 · Cited by 24 · cited 2× · see citing works
“…that an age-dependent increase in homeostatic proliferation via IL-6–mediated IL-7 expression plays a role in the accumulation of antigen-experienced memory/activated T cells in many class II MHC–associated diseases have not been well established (Mocci et al., 2000; Skapenko et al., 2005).”
Ishihara, K. (2004) · International Immunology · doi:10.1093/intimm/dxh045 · Cited by 21 · cited 1× · see citing works
“Indeed, forced expression of p40 Tax in F759 mice has been seen to enhance disease development (Ishihara et al., 2004).”
Self-citationOxazole-modified glycopeptides that target arthritis-associated class II MHC A(q) and DR4 proteins.
Andersson, I. E., Batsalova, T., Dzhambazov, B., Edvinsson, L., Holmdahl, R., Kihlberg, J., & Linusson, A. (2010) · Organic and biomolecular chemistry · doi:10.1039/c003640d · Cited by 20 · cited 1× · see citing works
“Furthermore, immunodominant MHC class II peptides in a collagen-induced arthritis model have been found to match those seen in human RA (Andersson et al., 2010), although whether these peptides are a result rather than a cause of joint damage is unclear.”
Intracellular Cytokine Staining
Scheibenbogen, C., Letsch, A., Asemissen, A., Schmittel, A., Thiel, E., & Keilholz, U. (2005) · doi:10.1007/1-4020-3623-x_9 · Cited by 19
Immune receptor signaling: from ubiquitination to NF-κB activation
Sun, S.-C. (2012) · Cellular & Molecular Immunology · doi:10.1038/cmi.2011.57 · Cited by 3 · see citing works
Flagged first, then by citations
5 of the 74 references couldn’t be matched to a known paper.
Research works printed but not linked: 5
- Bettelli E. Oukka M. Kuchroo V.K. 2007 T(H)-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8: 345– 350 10.1038/ni0407-345 17375096 · DOI
- Imboden J.B. 2009 The immunopathogenesis of rheumatoid arthritis. Annu. Rev. Pathol. 4: 417– 434 10.1146/annurev.pathol.4.110807.092254 18954286 · DOI
- O’Shea J.J. Ma A. Lipsky P. 2002 Cytokines and autoimmunity. Nat. Rev. Immunol. 2: 37– 45 10.1038/nri702 11905836 · DOI
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Cited by
Sorted by citations
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“These results suggest even T-cell-dependent tissue-specific autoimmune diseases do not necessarily require antigen-specific T cells (52).”
BackgroundResultInfluentialSelf-citationPathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis
Komatsu, N., Okamoto, K., Sawa, S., Nakashima, T., Oh-hora, M., Kodama, T., Tanaka, S., Bluestone, J. A., & Takayanagi, H. (2014) · Nature Medicine · doi:10.1038/nm.3432 · Cited by 1,153 · see citing works
Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice
Li, J., Sung, C. Y. J., Lee, N. P. Y., Ni, Y., Pihlajamäki, J., Panagiotou, G., & El-Nezami, H. S. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1518189113 · Cited by 624 · see citing works
“In these studies, Th17 cells are homed from gut to distant inflammatory sites, such as the nervous system (35) and joints (36).”
BackgroundPleiotropy and specificity: insights from the interleukin 6 family of cytokines
Murakami, M., Kamimura, D., & Hirano, T. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.027 · Cited by 533 · see citing works
Self-citationMori, T., Miyamoto, T., Yoshida, H., Asakawa, M., Kawasumi, M., Kobayashi, T., Morioka, H., Chiba, K., Toyama, Y., & Yoshimura, A. (2011) · International Immunology · doi:10.1093/intimm/dxr077 · Cited by 328 · see citing works
Arima, Y., Harada, M., Kamimura, D., Park, J.-H., Kawano, F., Yull, F. E., Kawamoto, T., Iwakura, Y., Betz, U. A. K., Márquez, G., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.022 · Cited by 307 · see citing works
“We have previously shown that Th17 cells accumulate in joints in a manner dependent on activating the IL-6 amplifier (Murakami et al., 2011), suggesting that the amplifier might be involved in the above accumulation.”
InfluentialSelf-citationInflammation amplifier, a new paradigm in cancer biology
Atsumi, T., Singh, R., Sabharwal, L., Bando, H., Meng, J., Arima, Y., Yamada, M., Harada, M., Jiang, J.-J., Kamimura, D., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2322 · Cited by 217 · see citing works
Self-citationLee, A., Qiao, Y., Grigoriev, G., Chen, J., Park‐Min, K., Park, S. H., Ivashkiv, L. B., & Kalliolias, G. D. (2013) · Arthritis & Rheumatism · doi:10.1002/art.37853 · Cited by 155 · see citing works
Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities
Miljkovic, D., & Spasojević, I. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.5068 · Cited by 124 · see citing works
“Reboldi et al . also found CCR6 + T cells in early cortical lesions, which implies that T cells infiltrate CSF using choroid plexus/CCL20 route (377) and may proceed to the cortex by provoking IL-17-dependent redistribution of CCL20 on the walls of blood vessels (103).”
InfluentialDisease-association analysis of an inflammation-related feedback loop
Murakami, M., Harada, M., Kamimura, D., Ogura, H., Okuyama, Y., Kumai, N., Okuyama, A., Singh, R., Jiang, J.-J., Atsumi, T., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.01.028 · Cited by 110 · see citing works
Self-citationRegulation of CCL20 expression in astrocytes by IL‐6 and IL‐17
Meares, G. P., Ma, X., Qin, H., & Benveniste, E. N. (2012) · Glia · doi:10.1002/glia.22307 · Cited by 113 · see citing works
“Enhancement of the IL-6 positive-feedback loop by IL-17 contributes to disease in murine models of autoimmune arthritis and EAE, suggesting a general role for the cooperative signaling between IL-6 and IL-17 in promotion of autoimmune diseases (Ogura et al., 2008).”
BackgroundKomatsu, N., & Takayanagi, H. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00077 · Cited by 98 · see citing works
“In contrast, in the arthritis of F759 mice, the recognition of joint antigens by CD4+T-cells may not be required, because F759 mice expressing a single TCR variant that recognizes a non-joint antigen do indeed develop arthritis (Murakami et al., 2011).”
InfluentialKomatsu, N., & Takayanagi, H. (2012) · Advances in immunology · doi:10.1016/b978-0-12-394299-9.00002-3 · Cited by 88 · see citing works
“In contrast, in the arthritis which occurs in F759mice, recognition of joint antigen may not be required, because F759 mice expressing a single TCR variant that recognizes a nonjoint antigen develop arthritis (Murakami et al., 2011).”
NEDD4 Is Involved in Inflammation Development during Keloid Formation
Fujita, M., Yamamoto, Y., Jiang, J., Atsumi, T., Tanaka, Y., Ohki, T., Murao, N., Funayama, E., Hayashi, T., Osawa, M., et al. (2018) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2018.07.044 · Cited by 93 · see citing works
Self-citationAnderson, A., Pratt, A., Sedhom, M. A. K., Doran, J., Routledge, C., Hargreaves, B., Brown, P., Cao, K., Isaacs, J., & Thomas, R. (2015) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2014-205850 · Cited by 78 · see citing works
Seronegative rheumatoid arthritis: pathogenetic and therapeutic aspects.
Pratt, A., & Isaacs, J. (2014) · Baillière's Best Practice & Research : Clinical Rheumatology · doi:10.1016/j.berh.2014.10.016 · Cited by 78 · see citing works
Stoop, J., Robinson, J., & Hilkens, C. (2011) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2011.151654 · Cited by 75 · see citing works
“The mechanisms by which TolDC induce tolerance include (1) deletion of T cells; (2) induction of T cell hyporesponsiveness; (3) deviation of the T cell cytokine profi le (eg, from T helper type 1 (Th1) to T helper type 2 (Th2)); and (4) induction of regulatory T cells (Tregs).”
BackgroundTemporal Expression of Growth Factors Triggered by Epiregulin Regulates Inflammation Development
Harada, M., Kamimura, D., Arima, Y., Kohsaka, H., Nakatsuji, Y., Nishida, M., Atsumi, T., Meng, J., Bando, H., Singh, R., et al. (2015) · Journal of Immunology · doi:10.4049/jimmunol.1400562 · Cited by 72 · see citing works
“1E, 1F), which are essential for the development of arthritis (4, 10).”
BackgroundMethodInfluentialSelf-citationPacheco, K. (2015) · Journal of Allergy and Clinical Immunology: In Practice · doi:10.1016/j.jaip.2015.07.011 · Cited by 71
Lee, J., Nakagiri, T., Oto, T., Harada, M., Morii, E., Shintani, Y., Inoue, M., Iwakura, Y., Miyoshi, S., Okumura, M., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103613 · Cited by 72 · see citing works
“The IL-6 amplifier, which synergistically activates NF-kB and STAT3 in type 1 collagen cells, causes inflammation by hyperexpressing chemokines (13, 15).”
BackgroundMethodSelf-citationThe Pathological and Physiological Roles of IL-6 Amplifier Activation
Murakami, M., & Hirano, T. (2012) · International Journal on Biological Sciences · doi:10.7150/ijbs.4828 · Cited by 69 · see citing works
“We have since shown in animal models for rheumatoid arthritis, multiple sclerosis (MS), and chronic rejection after transplantation that the IL-6 amplifier is stimulated by simultaneous activation of NFκB and STAT3, functions as a local inducer of chemokines, and acts as a mechanism for the local inflammation [13, 20-…”
BackgroundMethodInfluentialSelf-citationWilde, B., Thewissen, M., Damoiseaux, J., Hilhorst, M., van Paassen, P., Witzke, O., & Tervaert, J. C. (2012) · Arthritis Research & Therapy · doi:10.1186/ar4066 · Cited by 68 · see citing works
“suggests that antigen specificity of Th17 cells is of limited importance for the initiation of autoimmune processes [27,28].”
BackgroundArima, Y., Kamimura, D., Atsumi, T., Harada, M., Kawamoto, T., Nishikawa, N., Stofkova, A., Ohki, T., Higuchi, K., Morimoto, Y., et al. (2015) · eLife · doi:10.7554/elife.08733 · Cited by 66 · see citing works
“In this system, massive chemokine expression caused by the simultaneous stimulation of NFkB and STAT3 is followed by disruption of local homeostasis due to the local accumulation of various immune cells ( Murakami and Hirano, 2011 ; Murakami et al., 2011 ; Lee et al., 2012 , 2013 ).”
BackgroundSelf-citationRole of Complement Activation in Obliterative Bronchiolitis Post Lung Transplantation
Suzuki, H., Lasbury, M. E., Fan, L., Vittal, R., Mickler, E., Benson, H. L., Shilling, R., Wu, Q., Weber, D., Wagner, S., et al. (2013) · Journal of Immunology · doi:10.4049/jimmunol.1202242 · Cited by 60 · see citing works
“(45) suggests that Th17 development and IL-17a–mediated complement activation can be initiated in the absence of a humoral immune response.”
BackgroundMurakami, M., & Hirano, T. (2011) · Frontiers in Immunology · doi:10.3389/fimmu.2011.00022 · Cited by 53 · see citing works
“chronic inflammations in tissue-specific MHC class”
InfluentialSelf-citationPsoriatic inflammation facilitates the onset of arthritis in a mouse model.
Yamamoto, M., Nakajima, K., Takaishi, M., Kitaba, S., Magata, Y., Kataoka, S., & Sano, S. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.426 · Cited by 49 · see citing works
Trinschek, B., Lüssi, F., Haas, J., Wildemann, B., Zipp, F., Wiendl, H., Becker, C., & Jonuleit, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077634 · Cited by 49 · see citing works
“independent of T cell antigen specificity [45].”
Autoimmune disorder phenotypes in Hvcn1-deficient mice.
Sasaki, M., Tojo, A., Okochi, Y., Miyawaki, N., Kamimura, D., Yamaguchi, A., Murakami, M., & Okamura, Y. (2013) · Biochemical Journal · doi:10.1042/bj20121188 · Cited by 41 · see citing works
Self-citationIL-6 amplifier activation in epithelial regions of bronchi after allogeneic lung transplantation.
Lee, J.-Y., Nakagiri, T., Kamimura, D., Harada, M., Oto, T., Susaki, Y., Shintani, Y., Inoue, M., Miyoshi, S., Morii, E., et al. (2013) · International Immunology · doi:10.1093/intimm/dxs158 · Cited by 40 · see citing works
Self-citationCordova, K. N., Willis, V., Haskins, K., & Holers, V. (2013) · Journal of Immunology · doi:10.4049/jimmunol.1201517 · Cited by 39
“An alternative explanation for enhanced arthritis in this study is that HCF4Vb7 CD4 T cells act as a local source of IL-17 in the joint, as reported previously (61).”
BackgroundAdvances in Rheumatoid Arthritis Animal Models
Moudgil, K., Kim, P., & Brahn, E. (2011) · Current Rheumatology Reports · doi:10.1007/s11926-011-0200-z · Cited by 34
Rbm10 regulates inflammation development via alternative splicing of Dnmt3b
Atsumi, T., Suzuki, H., Jiang, J., Okuyama, Y., Nakagawa, I., Ota, M., Tanaka, Y., Ohki, T., Katsunuma, K., Nakajima, K., et al. (2017) · International Immunology · doi:10.1093/intimm/dxx067 · Cited by 41 · see citing works
Self-citationHutchins, A. P., Diez, D., & Miranda-Saavedra, D. (2013) · JAK-STAT · doi:10.4161/jkst.25097 · Cited by 31 · see citing works
“37,38 Opposing effects of STAT3 have also been described within the same cell type: in DCs, the IL-6-mediated pro-inflammatory activity of STAT3 appears to be rapidly induced, followed by a decline, whereas the IL-10-mediated Figure 1.”
BackgroundTakada, Y., Kamimura, D., Jiang, J.-J., Higuchi, H., Iwami, D., Hotta, K., Tanaka, Y., Ota, M., Higuchi, M., Nishio, S., et al. (2020) · International Immunology · doi:10.1093/intimm/dxaa032 · Cited by 31 · see citing works
Self-citationSabharwal, L., Kamimura, D., Meng, J., Bando, H., Ogura, H., Nakayama, C., Jiang, J., Kumai, N., Suzuki, H., Atsumi, T., et al. (2014) · The Journal of Biochemistry · doi:10.1093/jb/mvu057 · Cited by 34 · see citing works
Self-citationŠtofková, A., Kamimura, D., Ohki, T., Ota, M., Arima, Y., & Murakami, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-38895-y · Cited by 35 · see citing works
Self-citationOta, M., Tanaka, Y., Nakagawa, I., Jiang, J.-J., Arima, Y., Kamimura, D., Onodera, T., Iwasaki, N., & Murakami, M. (2019) · Arthritis & Rheumatology · doi:10.1002/art.41182 · Cited by 28 · see citing works
“were evaluated as previously described (24).”
MethodSelf-citationThe gateway theory: bridging neural and immune interactions in the CNS
Kamimura, D., Yamada, M., Harada, M., Sabharwal, L., Meng, J., Bando, H., Ogura, H., Atsumi, T., Arima, Y., & Murakami, M. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00204 · Cited by 35 · see citing works
Self-citationTamura, Y., Ohta, H., Torisu, S., Yuki, M., Yokoyama, N., Murakami, M., Lim, S., Osuga, T., Morishita, K., Nakamura, K., et al. (2013) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2013.09.017 · Cited by 27 · see citing works
Self-citationProliferative Pathways of Vascular Smooth Muscle Cells in Response to Intermittent Hypoxia
Kyotani, Y., Takasawa, S., & Yoshizumi, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112706 · Cited by 24 · see citing works
Model answers: Rational application of murine models in arthritis research
Benson, R., McInnes, I., Garside, P., & Brewer, J. (2017) · European Journal of Immunology · doi:10.1002/eji.201746938 · Cited by 26
Arleevskaya, M., Gabdoulkhakova, A., Filina, Y. V., Miftakhova, R., Bredberg, A., & Tsybulkin, A. P. (2014) · BMJ Open · doi:10.1136/bmjopen-2014-005254 · Cited by 26 · see citing works
Anderson, A., Maney, N., Nair, N., Lendrem, D., Skelton, A., Diboll, J., Brown, P., Smith, G. R., Carmody, R., Barton, A., et al. (2019) · Rheumatology · doi:10.1093/rheumatology/kez003 · Cited by 24 · see citing works
Role of Suppressors of Cytokine Signaling 3 in Bone Inflammatory Responses
Gao, A., & Dyke, T. V. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00506 · Cited by 24 · see citing works
“Recent studies demonstrate that T helper 17 (Th17) cells play a critical role in the development of arthritis (39, 40).”
BackgroundWilson, C., Hine, D. W., Pradipta, A., Pearson, J., van Eden, W., Robinson, J., & Knight, A. M. (2012) · Immunology · doi:10.1111/j.1365-2567.2011.03548.x · Cited by 24 · see citing works
Oh, S., Aitken, M., Simons, D. M., Basehoar, A., Garcia, V., Kropf, E., & Caton, A. (2012) · Journal of Immunology · doi:10.4049/jimmunol.1103598 · Cited by 24 · see citing works
Yahagi, A., Saika, T., Hirano, H., Takai-Imamura, M., Tsuji, F., Aono, H., Iseki, M., Morita, Y., Igarashi, H., Saeki, Y., et al. (2019) · RMD Open · doi:10.1136/rmdopen-2018-000853 · Cited by 22 · see citing works
Breakpoint Cluster Region–Mediated Inflammation Is Dependent on Casein Kinase II
Meng, J., Jiang, J.-J., Atsumi, T., Bando, H., Okuyama, Y., Sabharwal, L., Nakagawa, I., Higuchi, H., Ota, M., Okawara, M., et al. (2016) · Journal of Immunology · doi:10.4049/jimmunol.1601082 · Cited by 22 · see citing works
Self-citationMany Roles of CCL20: Emphasis on Breast Cancer
Osuala, K. O., & Sloane, B. F. (2014) · Postdoc Journal · doi:10.14304/surya.jpr.v2n3.2 · Cited by 19 · see citing works
Splenic Stromal Cells from Aged Mice Produce Higher Levels of IL-6 Compared to Young Mice
Park, J., Miyakawa, T., Shiokawa, A., Nakajima‐Adachi, H., Tanokura, M., & Hachimura, S. (2014) · Mediators of Inflammation · doi:10.1155/2014/826987 · Cited by 20 · see citing works
“It implies that IL6 is a critical factor in autoimmune diseases, especially in rheumatoid arthritis [29–31].”
Higuchi, H., Kamimura, D., Jiang, J., Atsumi, T., Iwami, D., Hotta, K., Harada, H., Takada, Y., Kanno‐Okada, H., Hatanaka, K. C., et al. (2020) · International Immunology · doi:10.1093/intimm/dxaa003 · Cited by 27 · see citing works
Self-citationStudy of some immunological effects of methotrexate in people with rheumatoid arthritis
Kareem, F., & Thamer, W. (2019) · Al-Qadisiyah Journal Of Pure Science · doi:10.29350/jops.2019.24.2.957 · Cited by 19
ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons
Hasebe, R., Murakami, K., Harada, M., Halaka, N., Nakagawa, H., Kawano, F., Ohira, Y., Kawamoto, T., Yull, F. E., Blackwell, T. S., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20212019 · Cited by 21 · see citing works
Self-citationSjHSP60 induces CD4+CD25+Foxp3+ Tregs via TLR4-Mal-drived production of TGF-β in macrophages
Zhou, S., Qi, Q.-Q., Wang, X.-F., Zhang, L.-N., Xu, L., Dong, L.-Y., Zhu, J.-F., Li, Y., Wang, X.-F., Xu, Z.-P., et al. (2018) · Immunology and Cell Biology · doi:10.1111/imcb.12160 · Cited by 18
“The previously described primers used for qPCR are listed in Supplementary table 2.(45-54)”
MethodInoue, A., Matsumoto, I., Tanaka, Y., Umeda, N., Tanaka, Y., Mihara, M., Takahashi, S., & Sumida, T. (2012) · Arthritis & Rheumatism · doi:10.1002/art.34666 · Cited by 18 · see citing works
“In addition to Th17 cells, the importance of IL-6/STAT-3 signals in type I collagen fibroblasts was recently proven in this model (23).”
BackgroundKyotani, Y., Itaya-Hironaka, A., Yamauchi, A., Sakuramoto-Tsuchida, S., Makino, M., Takasawa, S., & Yoshizumi, M. (2018) · FEBS Open Bio · doi:10.1002/2211-5463.12430 · Cited by 17 · see citing works
The Gateway Reflex, a Novel Neuro-Immune Interaction for the Regulation of Regional Vessels
Tanaka, Y., Arima, Y., Kamimura, D., & Murakami, M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01321 · Cited by 19 · see citing works
Self-citationThe Role of the Transcriptional Regulation of Stromal Cells in Chronic Inflammation
Valín, Á., & Pablos, J. L. (2015) · Biomolecules · doi:10.3390/biom5042723 · Cited by 16 · see citing works
“IL-17A and IL-6 also synergistically induced the expression of various NF- B target genes, including chemokines as CCL20, CXCL1, CXCL2, KC, MIP2, and I B-z [86,87].”
BackgroundMechanisms of autoimmunity in human diseases: a critical review of current dogma
Benson, R., Brewer, J., & Platt, A. M. (2014) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000037 · Cited by 17 · see citing works
“Whether this requires jointspecific trauma or stress to induce cellular traffic through the joint or results from constitutive cellular recirculation can probably only be revealed through animal models [33].”
BackgroundMurakami, M., Arima, Y., Ogura, H., & Kamimura, D. (2013) · Biomedical Journal · doi:10.4103/2319-4170.113187 · Cited by 16 · see citing works
Self-citationBmi1 Regulates IκBα Degradation via Association with the SCF Complex
Okuyama, Y., Tanaka, Y., Jiang, J.-J., Kamimura, D., Nakamura, A., Ota, M., Ohki, T., Higo, D., Ogura, H., Ishii, N., et al. (2018) · Journal of Immunology · doi:10.4049/jimmunol.1701223 · Cited by 16 · see citing works
Self-citationTanaka, Y., Sabharwal, L., Ota, M., Nakagawa, I., Jiang, J.-J., Arima, Y., Ogura, H., Okochi, M., Ishii, M., Kamimura, D., et al. (2018) · Journal of Immunology · doi:10.4049/jimmunol.1701446 · Cited by 16 · see citing works
Self-citationIn vivo regulation of gene expression and T helper type 17 differentiation by RORγt inverse agonists
Skepner, J. E., Trocha, M., Ramesh, R., Qu, X. A., Schmidt, D. R., Baloglu, E., Lobera, M., Davis, S. P., Nolan, M. A., Carlson, T. J., et al. (2015) · Immunology · doi:10.1111/imm.12444 · Cited by 16 · see citing works
Targeting of Interleukin-6 for the Treatment of Rheumatoid Arthritis: A Review and Update
Tanaka, T., Ogata, A., & Kishimoto, T. (2014) · doi:10.4172/2161-1149.s4-002 · Cited by 15
“The IL-6 amplifier loop, which features an age-dependent increase in Th17 cells, excessive IL-6 production, and is a positive feedback loop for NF-κB signaling, as well as a signal transducer and activator of transcription (STAT)3 activation in non-immune cells, has been shown to be responsible for the development of…”
BackgroundSimons, D. M., Oh, S., Kropf, E., Aitken, M., Garcia, V., Basehoar, A., & Caton, A. (2013) · Journal of Immunology · doi:10.4049/jimmunol.1203212 · Cited by 13
Gateway reflex: neural activation-mediated immune cell gateways in the central nervous system
Kamimura, D., Ohki, T., Arima, Y., & Murakami, M. (2018) · International Immunology · doi:10.1093/intimm/dxy034 · Cited by 12 · see citing works
Self-citationChen, F., Ye, W., Wang, Q., Zhao, L., Liang, M.-R., Zheng, S., Zhao, T.-Y., Xuan, D.-D., Zhu, Z.-H., Yu, Y.-Y., et al. (2025) · Clinical Rheumatology · doi:10.1007/s10067-025-07433-9 · Cited by 10 · see citing works
Dey, I., & Bishayi, B. (2019) · Microbial Pathogenesis · doi:10.1016/j.micpath.2019.103903 · Cited by 9
Tanaka, H., Hasebe, R., Murakami, K., Sugawara, T., Yamasaki, T., & Murakami, M. (2023) · Bioelectronic Medicine · doi:10.1186/s42234-023-00126-1 · Cited by 7 · see citing works
“In F759 mice, arthritis can be rapidly induced by administering IL-6 and IL-17A to the joints (Harada et al. 2015; Murakami et al. 2011).”
BackgroundSelf-citationArthritis in space and time – To boldly go!
Benson, R. A., Patakas, A., McQueenie, R., Ross, K., McInnes, I. B., Brewer, J. M., & Garside, P. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.04.069 · Cited by 8 · see citing works
IL-6 and Inflammatory Diseases
Kamimura, D., Arima, Y., Hirano, T., Ogura, H., & Murakami, M. (2013) · Springer eBooks · doi:10.1007/978-4-431-54442-5_2 · Cited by 8 · see citing works
Self-citationFrey, O., Hückel, M., Gajda, M., Petrow, P., & Bräuer, R. (2018) · Arthritis Research & Therapy · doi:10.1186/s13075-018-1720-y · Cited by 7
“Overexpression of TNF or enhanced IL-6 signaling due to a gain-of-function mutation of gp130 is sufficient to induce arthritis in mice [31, 32].”
BackgroundYano, A., Yuki, S., Shiraishi, A., Hakozaki, M., Kanno, Y., Ken-ichi, K., & Uesugi, S. (2023) · Bioscience, biotechnology and biochemistry · doi:10.1093/bbb/zbad070 · Cited by 5 · see citing works
Gateway reflex: Local neuroimmune interactions that regulate blood vessels
Kamimura, D., Ohki, T., Arima, Y., Ota, M., & Murakami, M. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.09.011 · Cited by 5 · see citing works
Self-citationIshihara, K., & Igarashi, H. (2012) · InTech eBooks · doi:10.5772/29113 · Cited by 5 · see citing works
“, 2004), and also the mechanisms for initiation or perpetuation of joint inflammation (Murakami et al., 2011; Ogura et al., 2008).”
BackgroundAkabane, K., Murakami, K., & Murakami, M. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2225215 · Cited by 1 · see citing works
Self-citationSritharan, S., Kannan, T., Norazmi, M., & Nurul, A. (2016) · International Journal of Peptide Research and Therapeutics · doi:10.1007/s10989-016-9529-5 · Cited by 3 · see citing works
“Identifying such functional cytokines involved in these mechanisms have been widely studied (Horowitz and Lorenzo 2008; Lorenzo 2011; Murakami et al. 2011).”
Leavy, O. (2011) · Nature Reviews Immunology · doi:10.1038/nri2933 · Cited by 3 · see citing works
The gateway reflex: breaking through the blood barriers
Murakami, K., Tanaka, Y., & Murakami, M. (2021) · International Immunology · doi:10.1093/intimm/dxab064 · Cited by 1 · see citing works
Self-citationImmunosenescence, immunotolerance and rejection: clinical aspects in solid organ transplantation
Rubino, G., & Yörük, E. (2024) · Transplant Immunology · doi:10.1016/j.trim.2024.102068 · Cited by 1 · see citing works
Maeda, K., Ogawa, T., Kayama, T., Sasaki, T., Tainaka, K., Murakami, M., & Haseyama, M. (2024) · Bioengineering · doi:10.3390/bioengineering11060523 · Cited by 1 · see citing works
“Consequently, the injection of IL-6 and IL-17 into the ankle joints of F759 mice activates the IL-6 amplifier, improving the activation of the NFkB pathway in nonimmune cells, including synovial cells, ultimately resulting in the development of rheumatoid-like arthritis [23].”
BackgroundSelf-citationTeoh, Y. B., Jiang, J., Yamasaki, T., Nagata, N., Sugawara, T., Hasebe, R., Ohta, H., Sasaki, N., Yokoyama, N., Nakamura, K., et al. (2023) · Frontiers in Veterinary Science · doi:10.3389/fvets.2023.1192888 · Cited by 2 · see citing works
Self-citationGateway Reflex: A Neuro-Immune Crosstalk for Organ-Specific Disease Development
Kamimura, D., Tanaka, Y., Ohki, T., & Murakami, M. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.77112 · Cited by 1 · see citing works
Self-citationPain is an inducer for relapse in multiple sclerosis models through a regional neural signal
Arima, Y., Higuchi, K., Nishikawa, N., Štofková, A., Ohki, T., Kamimura, D., & Murakami, M. (2015) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12250 · Cited by 2 · see citing works
Self-citationImmune cell gateways in the central nervous system regulated by regional neural stimulations
Kamimura, D., Štofková, A., Nishikawa, N., Atsumi, T., Arima, Y., & Murakami, M. (2015) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12198 · Cited by 1 · see citing works
“In addition, mice devoid of amplifier activation in non-immune cells are highly resistant to animal models of not only MS, but also RA and allogeneic graft rejection, showing that the inflammation amplifier is fundamental for many chronic inflammatory diseases in vivo.(26,44,46,48) The aforementioned observations sugg…”
BackgroundSelf-citationThe Reverse-Direction Method Links Mass Experimental Data to Human Diseases
Ogura, H., Atsumi, T., Bando, H., Sabharwal, L., Yamada, M., Jiang, J.-J., Nakamura, A., Arima, Y., Kamimura, D., & Murakami, M. (2013) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-013-0255-9 · Cited by 1 · see citing works
“1 was used as a cutoff for the bioinformatic results (Murakami et al. 2013). b A scheme of the reversedirection method Arch. Immunol. Ther. Exp. (2014) 62:41–45 43”
MethodSelf-citationImmunological Basis of Inflammatory Arthritides
Kalliolias, G., & Skokos, D. (2019) · Absolute Rheumatology Review · doi:10.1007/978-3-030-23022-7_1 · Cited by 1 · see citing works
Inflammation amplifier and gateway reflex: The regulation of inflammation by neuroimmune interaction
Nakagawa, I., & Murakami, M. (2017) · Japanese Journal of Clinical Immunology · doi:10.2177/jsci.40.160 · Cited by 2 · see citing works
Self-citationde Souza, K. S. S., de Almeida, A. C., de Oliveira, S. P., Brandi, I., Santos, S. S., da Fonseca, F. S. A., Santos, E. M. S., Oliveira, J. R., de Freitas, D. F., Lelis, D. D. F., et al. (2021) · Research Society and Development · doi:10.33448/rsd-v10i4.13826
Eldem, A., Ayna, T., Baran, M., Soyöz, M., & Pirim, I. (2021) · Journal of Pediatric Genetics · doi:10.1055/s-0041-1722856
Boettger, M., Krucker, S., Gajda, M., Schaible, H.-G., & Hilberg, T. (2013) · Arthritis Research & Therapy · doi:10.1186/ar4331
“Recently, Murakami nd coworkers could show that repeated microbleedings could facilitate autoimmune arthritis in an animal model, thereby aggravating inflammation [38].”
Singh, R. (2013) · International Journal of Genomic Medicine · doi:10.4172/2332-0672.1000106
Self-citationHiguchi, K., Kamimura, D., Štofková, A., Nishikawa, N., Ohki, T., Arima, Y., & Murakami, M. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-805298-3.00005-0
Self-citation
- Authors
- Murakami, M., Okuyama, Y., Ogura, H., Asano, S., Arima, Y., Tsuruoka, M., Harada, M., Kanamoto, M., Sawa, Y., Iwakura, Y., Takatsu, K., Kamimura, D., & Hirano, T.
- Affiliations
- Japan Science and Technology Agency (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Toyama Prefectural Institute for Pharmaceutical Research (JP)
- Corresponding author
- Hirano, Toshio
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2011-01-10
- Volume
- 208
- Issue
- 1
- Pages
- 103-114
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3023133
- OpenAlex
- W2099359816
- Cited by
- 100
- References
- 74
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 7 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 9 · 2018: 8 · 2017: 5 · 2016: 3 · 2015: 8 · 2014: 8 · 2013: 20 · 2012: 11
- FWCI
- 10.99
- Type
- journal article
- Language
- en
- Update notices
- correction (2012-11-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- experimental arthritis, MHC class II, CD4+ T cells, Th17 cells, IL-17A, interleukin-6, CCL20, STAT3 signaling, type I collagen, T cell accumulation, tissue-specific autoimmunity, T cell activation
- MeSH terms
- Animals, Antigens, Arthritis, Hemorrhage, Lymphocyte Activation, T-Lymphocytes, Signal Transduction, Interleukin-6, Interleukin-17, Mice, Th17 Cells
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