Date of Award
Doctor of Philosophy (PhD)
Circadian clocks are cell-autonomous molecular oscillators that generate and maintain a circadian rhythm, or the endogenous 24-hour cycle of physiological and behavioral processes present in organisms. Composed of interlocked transcription-translation feedback loops, these clocks control and synchronize myriad of biological functions with routine fluctuations in the environment, thus thought to provide anticipatory and optimal responses to external changes. This is particularly evident in the gastrointestinal tract as circadian rhythm has been associated with digestion, nutrient absorption, gut motility, and even fluctuations of the microbiome. Group 3 intestinal innate lymphoid cells (ILC3s) which include NKp46+ and NKp46– subsets are RORgt-dependent cytokine secreting lymphocytes that provide mucosal defense through production of interleukin-22 (IL-22) and IL-17. As tissue resident cells enriched in the gastrointestinal tract, ILC3s have been shown to regulate many aspects of both mucosal immunity and intestinal functions. While previous works have demonstrated that ILC3s highly express key clock regulators such as REV-ERBa, the circadian clock and its functions in ILC3s are undefined. Thus, we investigated whether ILC3s are also attuned to circadian rhythm and the role of REV-ERBa in ILC3 development and function.
We noted circadian oscillations in the expression of clock regulators and cytokines, such as REV-ERBa, IL-22, and IL-17. Furthermore, acute disruption of the circadian rhythm affected cytokine secretion by ILC3s. Because of prominent and rhythmic expression of REV-ERBa in ILC3s, we also investigated the impact of constitutive deletion of REV-ERBa. Development of the NKp46+ ILC3 subset was markedly impaired in REV-ERBa deficient mice due to increased inhibition of RORgt expression by NFIL3. However, the NKp46– ILC3 subsets were comparatively less affected, potentially due to compensatory expression of other clock genes. Lastly, IL-17 secretion was paradoxically increased as a result of loss of inhibition by REV-ERBa and overactive RORgt activity. We conclude that ILC3s are attuned to circadian rhythm, but clock regulator REV-ERBa also has circadian-independent impacts on ILC3 development and functions due to its roles in the regulation of RORgt.
Chair and Committee
Thomas P. Burris
Wang, Qianli, "Role of Circadian Rhythm and Clock Regulator REV-ERBa in Group 3 Innate Lymphoid Cells" (2022). Arts & Sciences Electronic Theses and Dissertations. 2692.
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