Editorial: Cytokines and Intestinal Mucosal Immunity (original) (raw)

2021, Frontiers in Immunology

Editorial on the Research Topic Cytokines and Intestinal Mucosal Immunity Since discovery of the prototypic cytokines, interleukin-1 (IL-1) and tumor necrosis factor-a (TNF), almost 50 years ago (1, 2), an explosion of information has followed regarding the biology of cytokines and their critical role(s) during health and disease. To date, 41 interleukins and more than 18 TNF superfamily (TNFSF) members have been described. Notably, in 1990, our group was one of the first to show that blockade of a single cytokine, i.e., IL-1, was effective in markedly reducing the severity of experimental colitis (3), laying the foundation to conceptualize that targeting of an individual cytokine could successfully impact the development and progression of a specific disease. The role of cytokines, in fact, has been particularly important in the gastrointestinal tract, both in maintaining homeostasis and during chronic inflammatory disorders, such as inflammatory bowel disease (IBD), wherein many cell types have the ability to both react to, and produce, cytokines in response to a variety of antigenic stimuli, dietary products, microbial components, and toxic agents. This wealth of new information has led to the approval of different anti-cytokine therapies, such as anti-TNF and anti-IL-12/23 monoclonal antibodies, for the treatment of both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD. In addition, novel small molecule inhibitors, such as those targeting the JAK/STAT pathway, and which possess broad anti-cytokine activity, are now available in the armamentarium of gastroenterologists to treat IBD. In this Research Topic, the role of canonical, and more novel, cytokines are discussed in the context of intestinal immunity and chronic gut inflammation. Three articles focus on the role(s) of TNFSF members (Li et al.; Valatas et al.; Giles et al.). Specifically, Li et al. and Valatas et al. report the importance of the TL1A (TNF-like ligand 1A, TNFSF15)/DR3 (death receptor 3,TNFRSF25) ligand-pair, for which increasing evidence suggests a critical role not only in the pathogenesis of IBD, but also in the development of gut fibrosis/fibrostenotic disease. These papers highlight TL1A/ DR3's pleiotropic functions in regulating the balance between T effector and T regulatory cells (Tregs), as well as innate lymphoid cells (ILCs), thereby serving as a vital rheostat during IBD. Notably, monoclonal antibodies against TL1A are currently in clinical trials for the treatment of CD and UC, and will shortly reveal the efficacy of anti-TL1A/DR3 strategies in IBD.