Research Projects

Ulcerative colitis (UC), a chronic disease is characterized by massive inflammation and ulcers in the colon. The pathology of UC involves a complex interplay between various immune cells, stromal cells, and the microbiota through soluble antimicrobial peptides, cytokines, and chemokines. Many studies have showed strong associations between advancement of UC, elevated levels of pro-inflammatory cytokines and neutrophil infiltration in the intestinal mucosa. Hence, unlike normal protective immunity where inflammation is terminated after the resolution of infection, UC is sustained by chronic inflammation. The pathophysiology of ulcerative colitis is caused by a dysregulated immune response that mainly involves T helper cells (particularly Th17) (1). IL-17A produced by Th17 cells promote pathology in a variety of autoimmune conditions, and new therapies targeting IL-17A or Th17 cells are proving highly effective (2). In the healthy state, Th17 cells maintain microbial homeostasis in mucosal sites and are important regulators of extracellular bacterial and fungal pathogens (3). It is believed that microbial dysbiosis in UC contributes to a maladaptive immune response that causes tissue damage and persistent inflammation. Another key factor, neutrophils play a key role in the pathophysiology of UC by initiating and maintaining inflammation. Strong evidence for a pathogenic role for neutrophils/NETs (neutrophil extracellular traps) in UC is provided by the increased circulating levels of markers of neutrophil activation, increased Neutrophil-to-lymphocyte ratio and NET proteins (e.g., neutrophil elastase and human neutrophil lipocalin) in the blood of patients with active UC (4, 5), which negatively correlate with clinical outcome in humans (6). Although neutrophils play a critical role in protecting the gut mucosa from infections, their overactivation, malfunction, and persistence cause tissue damage, inflammation, and the advancement of ulcerative colitis. Notwithstanding these developments, it is still unclear which particular bacterial strains cause IL-17A-mediated neutrophil recruitment in IBD and how environmental, genetic, and dietary factors alter this relationship. Furthermore, how dysbiosis (microbial imbalance) tilts this signaling network in favor of chronic inflammation and aids in the pathophysiology of IBD is yet unknown. Developing tailored medicines to better manage UC requires a comprehensive understanding of these cellular interactions and the molecular mechanisms that regulate the signaling of these pro-inflammatory cytokines leading to the UC. In principle, any molecule in that signaling pathway could potentially be a target of therapeutics. The main goal of this proposal is to understand the underlying crosstalk between of IL-17A-neutrophil axis and host-microbiome in the pathogenesis of UC, with the long-term objective of developing novel immunotherapies targeting this pathway or its downstream modulators.