Validation of RUNX1 as a potential target for treating circadian clock-induced obesity through preventing migration of group 3 innate lymphoid cells into intestine

Group 3 innate lymphoid cells (ILC3s) critically orchestrate host-microbe interactions in the healthy mammalian intestine and become substantially impaired in the context of inflammatory bowel disease (IBD). However, the molecular pathways controlling the homeostasis of ILC3s remain incompletely defined. Here, we identify that intestinal ILC3s are highly enriched in expression of genes involved in the circadian clock and exhibit diurnal oscillations of these pathways in response to light cues. Classical ILC3 effector functions also exhibited diurnal oscillations, and lineage-specific deletion of BMAL1, a master regulator of the circadian clock, resulted in markedly reduced ILC3s selectively in the intestine. BMAL1-deficient ILC3s exhibit impaired expression of Nr1d1 and Per3, hyperactivation of RORγt-dependent target genes, and elevated proapoptotic pathways. Depletion of the microbiota with antibiotics partially reduced the hyperactivation of BMAL1-deficient ILC3s and restored cellular homeostasis in the intestine. Last, ILC3s isolated from the inflamed intestine of patients with IBD exhibit substantial alterations in expression of several circadian-related genes. Our results collectively define that circadian regulation is essential for the homeostasis of ILC3s in the presence of a complex intestinal microbiota and that this pathway is disrupted in the context of IBD.

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Faculty Opinions recommendation of Anti-microbial Functions of Group 3 Innate Lymphoid Cells in Gut-Associated Lymphoid Tissues Are Regulated by G-Protein-Coupled Receptor 183.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733518679.793551473 ◽

2018 ◽

Author(s):

Andrea Reboldi

Keyword(s):

G Protein ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Lymphoid Tissues ◽

G Protein Coupled Receptor ◽

Group 3 ◽

G Protein Coupled

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Gata3 drives development of RORγt+ group 3 innate lymphoid cells

Journal of Experimental Medicine ◽

10.1084/jem.20131038 ◽

2014 ◽

Vol 211 (2) ◽

pp. 199-208 ◽

Cited By ~ 152

Author(s):

Nicolas Serafini ◽

Roel G.J. Klein Wolterink ◽

Naoko Satoh-Takayama ◽

Wei Xu ◽

Christian A.J. Vosshenrich ◽

...

Keyword(s):

T Cell ◽

Fetal Liver ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

T Cell Subsets ◽

Mucosal Barrier ◽

Hematopoietic Stem ◽

Mucosal Surfaces ◽

Gata3 Expression ◽

Group 3

Group 3 innate lymphoid cells (ILC3) include IL-22–producing NKp46+ cells and IL-17A/IL-22–producing CD4+ lymphoid tissue inducerlike cells that express RORγt and are implicated in protective immunity at mucosal surfaces. Whereas the transcription factor Gata3 is essential for T cell and ILC2 development from hematopoietic stem cells (HSCs) and for IL-5 and IL-13 production by T cells and ILC2, the role for Gata3 in the generation or function of other ILC subsets is not known. We found that abundant GATA-3 protein is expressed in mucosa-associated ILC3 subsets with levels intermediate between mature B cells and ILC2. Chimeric mice generated with Gata3-deficient fetal liver hematopoietic precursors lack all intestinal RORγt+ ILC3 subsets, and these mice show defective production of IL-22 early after infection with the intestinal pathogen Citrobacter rodentium, leading to impaired survival. Further analyses demonstrated that ILC3 development requires cell-intrinsic Gata3 expression in fetal liver hematopoietic precursors. Our results demonstrate that Gata3 plays a generalized role in ILC lineage determination and is critical for the development of gut RORγt+ ILC3 subsets that maintain mucosal barrier homeostasis. These results further extend the paradigm of Gata3-dependent regulation of diversified innate ILC and adaptive T cell subsets.

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