Circadian Clock Disruption Suppresses PDL1 Intraepithelial B Cells in Experimental Colitis and Colitis-Associated Colorectal Cancer

Overview

Journal Cell Mol Gastroenterol Hepatol

Specialty Gastroenterology

Date 2021 Mar 2

PMID 33652118

Citations 16

Authors

Jing-Lin Liu

Chu-Yi Wang

Tian-Yu Cheng

Youlutuziayi Rixiati

Cheng Ji

Min Deng

Su Yao

Li-Hua Yuan

Yuan-Yuan Zhao

Tong Shen

Jian-Ming Li

Affiliations

Soon will be listed here.

Abstract

Background & Aims: The circadian clock is crucial for physiological homeostasis including gut homeostasis. Disorder of the circadian clock may contribute to many diseases including inflammatory bowel disease (IBD). However, the role and the mechanisms of circadian clock involvement in IBD still are unclear.

Methods: Disorder of the circadian clock including chronic social jet lag and circadian clock gene deficiency mice (Bmal1, and Per1Per2) were established. Dextran sulfate sodium (DSS) and/or azoxymethane were used to induce mouse models of colitis and its associated colorectal cancer. Flow cytometry, immunohistochemistry, immunofluorescence, Western blot, and reverse-transcription quantitative polymerase chain reaction were used to analyze the characteristics of immune cells and their related molecules.

Results: Mice with disorders of the circadian clock including chronic social jet lag and circadian clock gene deficiency were susceptible to colitis. Functionally, regulatory B (Breg) cells highly expressing Programmed cell death 1 ligand 1 (PDL1) in intestinal intraepithelial lymphocytes (IELs) helped to alleviate the severity of colitis after DSS treatment and was dysregulated in DSS-treated Bmal1 mice. Notably, interleukin 33 in the intestinal microenvironment was key for Bmal1-regulated PDL1 Breg cells and interleukin 33 was a target of Bmal1 transcriptionally. Dysregulated PDL1 B cells induced cell death of activated CD4 T cells in DSS-treated Bmal1 mice. Consequently, circadian clock disorder was characterized as decreased numbers of Breg PDL1 cells in IELs and dysfunction of CD4 T cells promoted colitis-associated colorectal cancer (CRC) in mice. In clinical samples from CRC patients, low expression of Bmal1 gene in paracancerous tissues and center area of tumor was associated closely with a poorer prognosis of CRC patients.

Conclusions: Our study uncovers the importance of the circadian clock regulating PDL1 Breg cells of IELs in IBD and IBD-associated CRC.

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References

Kobori A, Yagi Y, Imaeda H, Ban H, Bamba S, Tsujikawa T . Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis. J Gastroenterol. 2010; 45(10):999-1007. DOI: 10.1007/s00535-010-0245-1. View

Mauri C, Bosma A . Immune regulatory function of B cells. Annu Rev Immunol. 2012; 30:221-41. DOI: 10.1146/annurev-immunol-020711-074934. View

Seregin S, Golovchenko N, Schaf B, Chen J, Pudlo N, Mitchell J . NLRP6 Protects Il10 Mice from Colitis by Limiting Colonization of Akkermansia muciniphila. Cell Rep. 2017; 19(4):733-745. PMC: 5528001. DOI: 10.1016/j.celrep.2017.03.080. View

Bamias G, Nyce M, De La Rue S, Cominelli F . New concepts in the pathophysiology of inflammatory bowel disease. Ann Intern Med. 2005; 143(12):895-904. DOI: 10.7326/0003-4819-143-12-200512200-00007. View

Ranjbaran Z, Keefer L, Farhadi A, Stepanski E, Sedghi S, Keshavarzian A . Impact of sleep disturbances in inflammatory bowel disease. J Gastroenterol Hepatol. 2007; 22(11):1748-53. DOI: 10.1111/j.1440-1746.2006.04820.x. View

Stokes K, Cooke A, Chang H, Weaver D, Breault D, Karpowicz P . The Circadian Clock Gene Coordinates Intestinal Regeneration. Cell Mol Gastroenterol Hepatol. 2017; 4(1):95-114. PMC: 5453906. DOI: 10.1016/j.jcmgh.2017.03.011. View

Deng W, Zhu S, Zeng L, Liu J, Kang R, Yang M . The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis. Cell Rep. 2018; 24(2):366-378. PMC: 6094382. DOI: 10.1016/j.celrep.2018.06.026. View

Carriere V, Roussel L, Ortega N, Lacorre D, Americh L, Aguilar L . IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci U S A. 2006; 104(1):282-7. PMC: 1765450. DOI: 10.1073/pnas.0606854104. View

Yu X, Wang Y, Deng M, Li Y, Ruhn K, Zhang C . The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. Elife. 2014; 3. PMC: 4356142. DOI: 10.7554/eLife.04406. View

10.

Papagiannakopoulos T, Bauer M, Davidson S, Heimann M, Subbaraj L, Bhutkar A . Circadian Rhythm Disruption Promotes Lung Tumorigenesis. Cell Metab. 2016; 24(2):324-31. PMC: 5367626. DOI: 10.1016/j.cmet.2016.07.001. View

11.

Mantis N, Forbes S . Secretory IgA: arresting microbial pathogens at epithelial borders. Immunol Invest. 2010; 39(4-5):383-406. PMC: 3774547. DOI: 10.3109/08820131003622635. View

12.

Hughes M, Hogenesch J, Kornacker K . JTK_CYCLE: an efficient nonparametric algorithm for detecting rhythmic components in genome-scale data sets. J Biol Rhythms. 2010; 25(5):372-80. PMC: 3119870. DOI: 10.1177/0748730410379711. View

13.

Swanson G, Burgess H . Sleep and Circadian Hygiene and Inflammatory Bowel Disease. Gastroenterol Clin North Am. 2017; 46(4):881-893. DOI: 10.1016/j.gtc.2017.08.014. View

14.

Song M, Hong C, Park S, Kim J, Yang B, Park Y . Protective effects of Fc-fused PD-L1 on two different animal models of colitis. Gut. 2014; 64(2):260-71. DOI: 10.1136/gutjnl-2014-307311. View

15.

Mazzoccoli G, Palmieri O, Corritore G, Latiano T, Bossa F, Scimeca D . Association study of a polymorphism in clock gene PERIOD3 and risk of inflammatory bowel disease. Chronobiol Int. 2012; 29(8):994-1003. DOI: 10.3109/07420528.2012.705935. View

16.

Preuss F, Tang Y, Laposky A, Arble D, Keshavarzian A, Turek F . Adverse effects of chronic circadian desynchronization in animals in a "challenging" environment. Am J Physiol Regul Integr Comp Physiol. 2008; 295(6):R2034-40. PMC: 2685296. DOI: 10.1152/ajpregu.00118.2008. View

17.

Hadden H, Soldin S, Massaro D . Circadian disruption alters mouse lung clock gene expression and lung mechanics. J Appl Physiol (1985). 2012; 113(3):385-92. PMC: 3426166. DOI: 10.1152/japplphysiol.00244.2012. View

18.

Pabst O . New concepts in the generation and functions of IgA. Nat Rev Immunol. 2012; 12(12):821-32. DOI: 10.1038/nri3322. View

19.

Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg R, Bhan A . Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity. 2002; 16(2):219-30. DOI: 10.1016/s1074-7613(02)00274-1. View

20.

Ananthakrishnan A, Long M, Martin C, Sandler R, Kappelman M . Sleep disturbance and risk of active disease in patients with Crohn's disease and ulcerative colitis. Clin Gastroenterol Hepatol. 2013; 11(8):965-71. PMC: 3659204. DOI: 10.1016/j.cgh.2013.01.021. View