Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis

Phosphodiesterase-4(PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate(c AMP) and inhibition of PDE4 has been proven to be a competitive strategy for dermatological and pulmonary inflammation. However, the pathological role of PDE4 and the therapeutic feasibility of PDE4 inhibitors in chronic ulcerative colitis(UC) are less clearly understood. This study introduced apremilast, a breakthrough in discovery of PDE4 inhibitors,to explore the therapeutic capacity in dextran sulfate sodium(DSS)-induced experimental murine chronic UC. In the inflamed tissues, overexpression of PDE4 isoforms and defective c AMP-mediating pathway were firstly identified in chronic UC patients. Therapeutically, inhibition of PDE4 by apremilast modulated c AMP-predominant protein kinase A(PKA)-c AMP-response element binding protein(CREB)signaling and ameliorated the clinical symptoms of chronic UC, as evidenced by improvements on mucosal ulcerations, tissue fibrosis, and inflammatory infiltrations. Consequently, apremilast maintained a normal intestinal physical and chemical barrier function and rebuilt the mucosal homeostasis by interfering with the cross-talk between human epithelial cells and immune cells. Furthermore, we found that apremilast could remap the landscape of gut microbiota and exert regulatory effects on antimicrobial responses and the function of mucus in the gut microenvironment. Taken together, the present studyrevealed that intervene of PDE4 provided an infusive therapeutic strategy for patients with chronic and relapsing UC.

Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity

A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota.An important next step is to elucidate a human-relevant"map"of microbiota-host interactions that regulate the metabolic health of the host.An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity.Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions,including cancer,neurodegeneration,and aging.The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood.Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage.Changes in the composition and function of the gut microbiota,i.e.,dysbiosis,are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction.Many effects of the microbiota on the host are mediated by microbiota-derived metabolites.In this review,we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases.The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.

Dichotomous roles of neutrophils in modulating pathogenic and repair processes of inflammatory bowel diseases

Neutrophils are considered as complex innate immune cells and play a critical role in maintaining intestinal mucosal homeostasis.They exert robust pro-inflammatory effects and recruit other immune cells in the acute phase of pathogen infection and intestinal inflammation,but paradoxically,they also limit exogenousmicrobial invasion and facilitate mucosal restoration.Hyperactivation or dysfunction of neutrophils results in abnormal immune responses,leading to multiple autoimmune and inflammatory diseases including systemic lupus erythematosus,rheumatoid arthritis,and inflammatory bowel diseases(IBD).As a refractory intestinal inflammatory disease,the pathogenesis and progression of IBD are associated with complicated immune response processes in which neutrophils are profoundly involved.However,the consensus on potential roles of neutrophils in modulating pathogenic and repair processes of IBD remains not fully understood.Accumulated infiltrating neutrophils cross the epithelial barrier and contribute to microbial dysbiosis,aggravated intestinal architectural damage,compromised resolution of intestinal inflammation and increased risk of thrombosis during IBD.Paradoxically,activated neutrophils are also associated with effective elimination of invaded microbiota,promoted angiogenesis and tissue restoration of gutmucosa in IBD.Here,we discuss the beneficial and detrimental roles of neutrophils in the onset and resolution of intestinalmucosal inflammation,hoping to provide a precise overview of neutrophil functions in the pathogenesis of IBD.