CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis

Masanori A. Murayama; Shigeru Kakuta; Asuka Inoue; Naoto Umeda; Tomo Yonezawa; Takumi Maruhashi; Koichiro Tateishi; Harumichi Ishigame; Rikio Yabe; Satoshi Ikeda; Akimasa Seno; Si Hua Chi; Yuriko Hashiguchi; Riho Kurata; Takuya Tada; Sachiko Kubo; Nozomi Sato; Yang Liu; Masahira Hattori; Shinobu Saijo; Misao Matsushita; Teizo Fujita; Takayuki Sumida; Yoichiro Iwakura

doi:10.1038/ncomms9483

CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis

Masanori A. Murayama, Shigeru Kakuta, Asuka Inoue, Naoto Umeda, Tomo Yonezawa, Takumi Maruhashi, Koichiro Tateishi, Harumichi Ishigame, Rikio Yabe, Satoshi Ikeda, Akimasa Seno, Si Hua Chi, Yuriko Hashiguchi, Riho Kurata, Takuya Tada, Sachiko Kubo, Nozomi Sato, Yang Liu, Masahira Hattori, Shinobu SaijoMisao Matsushita, Teizo Fujita, Takayuki Sumida, Yoichiro Iwakura

Research output: Contribution to journal › Article › peer-review

33 Citations (Scopus)

Abstract

The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6 -/- mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6-transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6 -/- mice and C1qtnf6 -/- embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H 2 O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases.

Original language	English
Article number	8483
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9483
Publication status	Published - Sep 25 2015
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms9483

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Murayama, M. A., Kakuta, S., Inoue, A., Umeda, N., Yonezawa, T., Maruhashi, T., Tateishi, K., Ishigame, H., Yabe, R., Ikeda, S., Seno, A., Chi, S. H., Hashiguchi, Y., Kurata, R., Tada, T., Kubo, S., Sato, N., Liu, Y., Hattori, M., ... Iwakura, Y. (2015). CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis. Nature communications, 6, [8483]. https://doi.org/10.1038/ncomms9483

CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis. / Murayama, Masanori A.; Kakuta, Shigeru; Inoue, Asuka; Umeda, Naoto; Yonezawa, Tomo; Maruhashi, Takumi; Tateishi, Koichiro; Ishigame, Harumichi; Yabe, Rikio; Ikeda, Satoshi; Seno, Akimasa; Chi, Si Hua; Hashiguchi, Yuriko; Kurata, Riho; Tada, Takuya; Kubo, Sachiko; Sato, Nozomi; Liu, Yang; Hattori, Masahira; Saijo, Shinobu; Matsushita, Misao; Fujita, Teizo; Sumida, Takayuki; Iwakura, Yoichiro.

In: Nature communications, Vol. 6, 8483, 25.09.2015.

Research output: Contribution to journal › Article › peer-review

Murayama, MA, Kakuta, S, Inoue, A, Umeda, N, Yonezawa, T, Maruhashi, T, Tateishi, K, Ishigame, H, Yabe, R, Ikeda, S, Seno, A, Chi, SH, Hashiguchi, Y, Kurata, R, Tada, T, Kubo, S, Sato, N, Liu, Y, Hattori, M, Saijo, S, Matsushita, M, Fujita, T, Sumida, T & Iwakura, Y 2015, 'CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis', Nature communications, vol. 6, 8483. https://doi.org/10.1038/ncomms9483

Murayama, Masanori A. ; Kakuta, Shigeru ; Inoue, Asuka ; Umeda, Naoto ; Yonezawa, Tomo ; Maruhashi, Takumi ; Tateishi, Koichiro ; Ishigame, Harumichi ; Yabe, Rikio ; Ikeda, Satoshi ; Seno, Akimasa ; Chi, Si Hua ; Hashiguchi, Yuriko ; Kurata, Riho ; Tada, Takuya ; Kubo, Sachiko ; Sato, Nozomi ; Liu, Yang ; Hattori, Masahira ; Saijo, Shinobu ; Matsushita, Misao ; Fujita, Teizo ; Sumida, Takayuki ; Iwakura, Yoichiro. / CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis. In: Nature communications. 2015 ; Vol. 6.

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title = "CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis",

abstract = "The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6 -/- mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6-transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6 -/- mice and C1qtnf6 -/- embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H 2 O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases.",

author = "Murayama, {Masanori A.} and Shigeru Kakuta and Asuka Inoue and Naoto Umeda and Tomo Yonezawa and Takumi Maruhashi and Koichiro Tateishi and Harumichi Ishigame and Rikio Yabe and Satoshi Ikeda and Akimasa Seno and Chi, {Si Hua} and Yuriko Hashiguchi and Riho Kurata and Takuya Tada and Sachiko Kubo and Nozomi Sato and Yang Liu and Masahira Hattori and Shinobu Saijo and Misao Matsushita and Teizo Fujita and Takayuki Sumida and Yoichiro Iwakura",

note = "Funding Information: We thank Dr Yuko Kimura and Dr Wen-Chao Song for assistance with the complement activation assay and Dr Junichi Miyazaki for the pCXN2 vector. We thank Dr Masato Nose for his excellent histological analysis of arthritis and thoughtful discussion. We thank Dr Shuhei Ogawa for an installation of C3−/− mice, and all the members of our laboratory for kind cooperation, discussion and animal care. This work was supported by CREST of the Japan Science and Technology Agency (to Y.I.), the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry (to Y.I.), Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (to Y.I.) and M.A.M. is a research assistant of the of the CREST program. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

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AU - Murayama, Masanori A.

AU - Kakuta, Shigeru

AU - Inoue, Asuka

AU - Umeda, Naoto

AU - Yonezawa, Tomo

AU - Maruhashi, Takumi

AU - Tateishi, Koichiro

AU - Ishigame, Harumichi

AU - Yabe, Rikio

AU - Ikeda, Satoshi

AU - Seno, Akimasa

AU - Chi, Si Hua

AU - Hashiguchi, Yuriko

AU - Kurata, Riho

AU - Tada, Takuya

AU - Kubo, Sachiko

AU - Sato, Nozomi

AU - Liu, Yang

AU - Hattori, Masahira

AU - Saijo, Shinobu

AU - Matsushita, Misao

AU - Fujita, Teizo

AU - Sumida, Takayuki

AU - Iwakura, Yoichiro

N1 - Funding Information: We thank Dr Yuko Kimura and Dr Wen-Chao Song for assistance with the complement activation assay and Dr Junichi Miyazaki for the pCXN2 vector. We thank Dr Masato Nose for his excellent histological analysis of arthritis and thoughtful discussion. We thank Dr Shuhei Ogawa for an installation of C3−/− mice, and all the members of our laboratory for kind cooperation, discussion and animal care. This work was supported by CREST of the Japan Science and Technology Agency (to Y.I.), the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry (to Y.I.), Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (to Y.I.) and M.A.M. is a research assistant of the of the CREST program. Publisher Copyright: © 2015 Macmillan Publishers Limited.

PY - 2015/9/25

Y1 - 2015/9/25

N2 - The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6 -/- mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6-transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6 -/- mice and C1qtnf6 -/- embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H 2 O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases.

AB - The complement system is important for the host defence against infection as well as for the development of inflammatory diseases. Here we show that C1q/TNF-related protein 6 (CTRP6; gene symbol C1qtnf6) expression is elevated in mouse rheumatoid arthritis (RA) models. C1qtnf6 -/- mice are highly susceptible to induced arthritis due to enhanced complement activation, whereas C1qtnf6-transgenic mice are refractory. The Arthus reaction and the development of experimental autoimmune encephalomyelitis are also enhanced in C1qtnf6 -/- mice and C1qtnf6 -/- embryos are semi-lethal. We find that CTRP6 specifically suppresses the alternative pathway of the complement system by competing with factor B for C3(H 2 O) binding. Furthermore, treatment of arthritis-induced mice with intra-articular injection of recombinant human CTRP6 cures the arthritis. CTRP6 is expressed in human synoviocytes, and CTRP6 levels are increased in RA patients. These results indicate that CTRP6 is an endogenous complement regulator and could be used for the treatment of complement-mediated diseases.

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CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis

Abstract

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