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

23 Scopus citations

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

Keywords

  • Autoimmune
  • B cell receptor
  • Cryptochrome

ASJC Scopus subject areas

  • General

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  • Cite this

    Cao, Q., Zhao, X., Bai, J., Gery, S., Sun, H., Lin, D. C., Chen, Q., Chen, Z., Mack, L., Yang, H., Deng, R., Shi, X., Chong, L. W., Cho, H., Xie, J., Li, Q. Z., Müschen, M., Atkins, A. R., Liddle, C., ... Koeffler, H. P. (2017). Circadian clock cryptochrome proteins regulate autoimmunity. Proceedings of the National Academy of Sciences of the United States of America, 114(47), 12548-12553. https://doi.org/10.1073/pnas.1619119114