Store-operated Calcium Entry (SOCE) as a regulator of adipocyte-T cell crosstalks in inflammatory bowel diseases

• Applicant: Dr. Carl Weidinger
• Subject Area: Gastroenterology ; Endocrinology, Diabetology, Metabolism ; Immunology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317963045

Adipose tissue not only controls the function and differentiation of lymphocytes through the secretion of adipokines, but adipocytes might also regulate antigen-specific immune responses by serving as antigen-presenting cells. The observation that bacteria as well as increased numbers of fat-infiltrating T cells can be found in the mesenteric adipose tissue of patients with Crohn's disease suggests that mesenteric adipose tissue might represent an important niche for adipocyte-immune cell interactions in inflammatory bowel disease (IBD). Despite first reports that a radical surgical resection of mesenteric adipose tissue may improve the remission-free survival of CD patients, the role of adipose tissue in the regulation of intestinal inflammatory responses is poorly understood. In particular, little is known about the molecular regulators of adipocyte-T cell interactions in IBD, and the signaling cascades orchestrating the interplay between adipocytes and T cells remain elusive. During the first funding period, we could identify store-operated calcium entry (SOCE) as a key signaling cascade controlling T cell differentiation and function in intestinal inflammation in mouse models as well as in IBD patients suggesting that the blockade of SOCE in lymphocytes might represent a promising new drug target for the treatment of therapy-refractory IBD patients. Since SOCE is also highly conserved in adipocytes and SOCE was shown to regulate the differentiation of adipocytes, we here hypothesize that SOCE serves as a central signaling pathway in adipocyte-T cell cross-talks thereby regulating adipocyte and T cell differentiation and their proinflammatory function in IBD. In Aim 1, we will use conditional knockout mouse models and human pre-adipocytes to investigate the role of SOCE in adipocyte homeostasis and in the inflammation-regulating function of adipocytes in intestinal inflammation. In Aim 2 we will then define how fat-secreted adipokines influence SOCE signaling activity in murine and human T cells. In Aim 3, we will investigate whether perturbations in the homeostasis of SOCE are observed in adipocytes and fat-residing T cells in surgical resectates obtained from IBD patients. Since pharmacological inhibitors of SOCE are currently being tested clinically for the treatment of excessive immune responses and SOCE inhibitors may also be used in the treatment of IBD patients in the future, the present project aims to investigate the role of SOCE in the interaction of adipocytes and T cells in IBD and aims to assess if SOCE represents a suitable drug target for the suppression of fat-mediated inflammation in IBD.

• DFG Programme: Research Grants