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PD-L1 Shapes B Cells as Safeguards in Circadian Clock Disorder
- Source :
- Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 2, Pp 783-784 (2021), Cellular and Molecular Gastroenterology and Hepatology
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
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 Per1-/-Per2-/-) 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.<br />Graphical abstract
- Subjects :
- PBL, peripheral blood lymphocyte
B Cells
Circadian clock
PBS, phosphate-buffered saline
IFNγ, interferon γ
RC799-869
SPL, spleen lymphocyte
B7-H1 Antigen
IM, invasive margin
AOM, azoxymethane
Text mining
FBS, fetal bovine serum
Circadian Clocks
PDL1
DSS, dextran sulfate sodium
PD-L1
CD, Crohn’s disease
TGFβ, transforming growth factor β
IEL, intraepithelial lymphocyte
MFI, mean fluorescence intensity
Th, T helper
Original Research
B-Lymphocytes
CT, tumor center
Hepatology
biology
business.industry
Gastroenterology
CJ, chronic jet lag
PDL1, Programmed cell death 1 ligand 1
MCP-1, monocyte chemoattractant protein-1
Diseases of the digestive system. Gastroenterology
Colitis
WT, wild-type
digestive system diseases
mRNA, messenger RNA
qRT-PCR, quantitative reverse-transcription polymerase chain reaction
IL, interleukin
ChIP, chromatin immunoprecipitation
Bmal1
Breg, regulatory B
UC, ulcerative colitis
CRC, colorectal cancer
biology.protein
Colitis-Associated Colorectal Cancer
DMEM, Dulbecco’s modified Eagle medium
GranzB, _
business
Neuroscience
Subjects
Details
- ISSN :
- 2352345X
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Cellular and Molecular Gastroenterology and Hepatology
- Accession number :
- edsair.doi.dedup.....ee9ae5c1618273438f02d3672f96f8aa