Innate lymphoid cells and cholesterol metabolism in intestinal barrier function

The intestinal mucosa represents one of the largest barrier sites of our body, having to withstand a constant exposure to a plethora of environmental insults (including dietary compounds, xenobiotics, metabolites and microorganisms). While our body has evolved tolerance/ignorance towards some of these factors deemed beneficial for the host, it requires constant maintenance of epithelial barrier integrity and ability to mount pro-inflammatory responses to protect against potentially harmful environmental insults. The intestinal epithelium and innate lymphoid cells (ILCs) are two fundamental players in safeguarding intestinal homeostasis. The goal of this thesis was to study how ILC development/functions and the regenerative capacity of the intestinal epithelium are shaped by the intestinal inflammatory and metabolic milieu.

In study I, we investigated whether the pool of adult ILC progenitors in the bone marrow was able to sense and respond to peripheral inflammation. We found that increase in systemic levels of the cytokine Flt3L resulted in expansion of ILC precursors committed to helper ILCs. Although ILCs expand in inflammatory bowel disease patients, this axis does not take place in response to intestinal inflammation. However, in the context of malaria, increased levels of systemic Flt3L correlated with expansion of bone marrow ILC precursors, thus suggesting a potential role for inflammatory ILC lymphopoiesis during malaria. In study II, we explored how alteration in cholesterol metabolism affected the function of intestinal ILCs. We showed that ILC3s, through the receptor EBI2, sensed cholesterol metabolites (oxysterols) produced by colonic stromal cells. Activation of this pathway led to ILC3 migration and thus formation of colonic lymphoid tissues (cryptopatches and isolated lymphoid follicles). Migration of ILC3s to cryptopatches resulted in their acquired ability to produce interleukin (IL)-22, a key intestinal homeostatic cytokine. However, in the context of colitis, augmented oxysterol production promoted EBI2-mediated inflammation and tissue remodeling.

In study III, we further investigated the contribution of cholesterol metabolism in intestinal physiology and found that a distinct oxysterol receptor (LXR) controlled the regenerative response of the intestinal epithelium. In the context of intestinal damage, oxysterol production and LXR activation was enhanced. Boosting activation of this pathway in intestinal epithelial cells enhanced regeneration in response to injury by promoting the activity of intestinal stem cells. Remarkably, in the context of tumor, LXR activation limited neoplastic progression, thus representing a novel promising therapeutic target to uncouple regeneration and tumorigenesis. Taken together, this thesis contributes to our understanding on how ILC and cholesterol metabolism modulate intestinal barrier function and integrity.

List of scientific papers

I. Parigi SM, Czarnewski P, Das S, Steeg C, Brockmann L, Fernandez-Gaitero S, Yman V, Forkel M, Höög C, Mjösberg J, Westerberg L, Färnert A, Huber S, Jacobs T, Villablanca EJ. Flt3 ligand expands bona fide innate lymphoid cell precursors in vivo. Scientific Reports. 2018 Jan 9;8(1):154.
https://doi.org/10.1038/s41598-017-18283-0

II. Emgård J, Kammoun H*, García-Cassani B*, Chesné J, Parigi SM, Jacob JM, Cheng HW, Evren E, Das S, Czarnewski P, Sleiers N, Melo-Gonzalez F, Kvedaraite E, Svensson M, Scandella E, Hepworth MR, Huber S, Ludewig B, Peduto L, Villablanca EJ, Veiga-Fernandes H, Pereira JP, Flavell RA, Willinger T. Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation. Immunity. 2018 Jan 16;48(1):120-132.e8. *Contributed equally.
https://doi.org/10.1016/j.immuni.2017.11.020

III. Das S*, Parigi SM*, Schewe M, Scharaw S, Webb A, Sorini C, Diaz O, Pelczar P, Frede A, Carrasco A, Pedrelli M, Andersson SJ, Czarnewski P, Nylen S, Antonson P, Mjösberg J, Gustafsson J-A, Gagliani N, Parini P, Huber S, Katajisto P, Villablanca EJ. Damage-induced Liver X Receptor activation promotes intestinal epithelial barrier regeneration. *Contributed equally. [Manuscript]