Circadian clock cryptochrome proteins regulate autoimmunity

Qi Cao, Xuan Zhao, Jingwen Bai, Sigal Gery, Haibo Sun, De Chen Lin, Qi Chen, Zhengshan Chen, Lauren Mack, Henry Yang, Ruishu Deng, Xianping Shi, Ling Wa Chong, Han Cho, Jianjun Xie, Quan Zhen Li, Markus Müschen, Annette R. Atkins, Christopher Liddle, Ruth T. YuSerhan Alkan, Jonathan W. Said, Ye Zheng, Michael Downes, Ronald M. Evans, H. Phillip Koeffler

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The circadian system regulates numerous physiological processes including immune responses. Here, we show that mice deficient of the circadian clock genes Cry1 and Cry2 [Cry double knockout (DKO)] develop an autoimmune phenotype including high serum IgG concentrations, serum antinuclear antibodies, and precipitation of IgG, IgM, and complement 3 in glomeruli and massive infiltration of leukocytes into the lungs and kidneys. Flow cytometry of lymphoid organs revealed decreased pre-B cell numbers and a higher percentage of mature recirculating B cells in the bone marrow, as well as increased numbers of B2 B cells in the peritoneal cavity of Cry DKO mice. The B cell receptor (BCR) proximal signaling pathway plays a critical role in autoimmunity regulation. Activation of Cry DKO splenic B cells elicited markedly enhanced tyrosine phosphorylation of cellular proteins compared with cells from control mice, suggesting that overactivation of the BCR-signaling pathway may contribute to the autoimmunity phenotype in the Cry DKO mice. In addition, the expression of C1q, the deficiency of which contributes to the pathogenesis of systemic lupus erythematosus, was significantly down-regulated in Cry DKO B cells. Our results suggest that B cell development, the BCR-signaling pathway, and C1q expression are regulated by circadian clock CRY proteins and that their dysregulation through loss of CRY contributes to autoimmunity.

Original languageEnglish (US)
Pages (from-to)12548-12553
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number47
DOIs
StatePublished - Nov 21 2017

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Cryptochromes
Circadian Clocks
Autoimmunity
B-Lymphocytes
Knockout Mice
Immunoglobulin G
Physiological Phenomena
Phenotype
Complement C3
B-Lymphoid Precursor Cells
Antinuclear Antibodies
Peritoneal Cavity
Serum
Systemic Lupus Erythematosus
Immunoglobulin M
Tyrosine
Flow Cytometry
Proteins
Leukocytes
Cell Count

Keywords

  • Autoimmune
  • B cell receptor
  • Cryptochrome

ASJC Scopus subject areas

  • General

Cite this

Circadian clock cryptochrome proteins regulate autoimmunity. / Cao, Qi; Zhao, Xuan; Bai, Jingwen; Gery, Sigal; Sun, Haibo; Lin, De Chen; Chen, Qi; Chen, Zhengshan; Mack, Lauren; Yang, Henry; Deng, Ruishu; Shi, Xianping; Chong, Ling Wa; Cho, Han; Xie, Jianjun; Li, Quan Zhen; Müschen, Markus; Atkins, Annette R.; Liddle, Christopher; Yu, Ruth T.; Alkan, Serhan; Said, Jonathan W.; Zheng, Ye; Downes, Michael; Evans, Ronald M.; Koeffler, H. Phillip.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 47, 21.11.2017, p. 12548-12553.

Research output: Contribution to journalArticle

Cao, Q, Zhao, X, Bai, J, Gery, S, Sun, H, Lin, DC, Chen, Q, Chen, Z, Mack, L, Yang, H, Deng, R, Shi, X, Chong, LW, Cho, H, Xie, J, Li, QZ, Müschen, M, Atkins, AR, Liddle, C, Yu, RT, Alkan, S, Said, JW, Zheng, Y, Downes, M, Evans, RM & Koeffler, HP 2017, 'Circadian clock cryptochrome proteins regulate autoimmunity', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 47, pp. 12548-12553. https://doi.org/10.1073/pnas.1619119114
Cao, Qi ; Zhao, Xuan ; Bai, Jingwen ; Gery, Sigal ; Sun, Haibo ; Lin, De Chen ; Chen, Qi ; Chen, Zhengshan ; Mack, Lauren ; Yang, Henry ; Deng, Ruishu ; Shi, Xianping ; Chong, Ling Wa ; Cho, Han ; Xie, Jianjun ; Li, Quan Zhen ; Müschen, Markus ; Atkins, Annette R. ; Liddle, Christopher ; Yu, Ruth T. ; Alkan, Serhan ; Said, Jonathan W. ; Zheng, Ye ; Downes, Michael ; Evans, Ronald M. ; Koeffler, H. Phillip. / Circadian clock cryptochrome proteins regulate autoimmunity. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 47. pp. 12548-12553.
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AU - Cao, Qi

AU - Zhao, Xuan

AU - Bai, Jingwen

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AU - Sun, Haibo

AU - Lin, De Chen

AU - Chen, Qi

AU - Chen, Zhengshan

AU - Mack, Lauren

AU - Yang, Henry

AU - Deng, Ruishu

AU - Shi, Xianping

AU - Chong, Ling Wa

AU - Cho, Han

AU - Xie, Jianjun

AU - Li, Quan Zhen

AU - Müschen, Markus

AU - Atkins, Annette R.

AU - Liddle, Christopher

AU - Yu, Ruth T.

AU - Alkan, Serhan

AU - Said, Jonathan W.

AU - Zheng, Ye

AU - Downes, Michael

AU - Evans, Ronald M.

AU - Koeffler, H. Phillip

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N2 - The circadian system regulates numerous physiological processes including immune responses. Here, we show that mice deficient of the circadian clock genes Cry1 and Cry2 [Cry double knockout (DKO)] develop an autoimmune phenotype including high serum IgG concentrations, serum antinuclear antibodies, and precipitation of IgG, IgM, and complement 3 in glomeruli and massive infiltration of leukocytes into the lungs and kidneys. Flow cytometry of lymphoid organs revealed decreased pre-B cell numbers and a higher percentage of mature recirculating B cells in the bone marrow, as well as increased numbers of B2 B cells in the peritoneal cavity of Cry DKO mice. The B cell receptor (BCR) proximal signaling pathway plays a critical role in autoimmunity regulation. Activation of Cry DKO splenic B cells elicited markedly enhanced tyrosine phosphorylation of cellular proteins compared with cells from control mice, suggesting that overactivation of the BCR-signaling pathway may contribute to the autoimmunity phenotype in the Cry DKO mice. In addition, the expression of C1q, the deficiency of which contributes to the pathogenesis of systemic lupus erythematosus, was significantly down-regulated in Cry DKO B cells. Our results suggest that B cell development, the BCR-signaling pathway, and C1q expression are regulated by circadian clock CRY proteins and that their dysregulation through loss of CRY contributes to autoimmunity.

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