Novel Distinct Roles for Intestinal/Macrophage Cyclooxygenase 2 and Apolipoprotein Mimetic Peptides in the Development and Treatment of Inflammatory Bowel Diseases

摘要

Cyclooxygenase 2 (COX2) has been associated with the development of inflammatory bowel disease (IBD), but the nature of this association has remained unclear. I demonstrate that mice that lack COX2 lose tolerance to pathogen associated molecular patterns. Thus, challenge with dietary cholate---an environmental trigger that I show impairs intestinal barrier function---induces severe intestinal inflammation in COX2 knock-out mice. COX2 knock-out within the myeloid compartment is sufficient to drive disease upon cholate challenge, while also altering upon disease the balance between pro-inflammatory and inflammation resolving mediators towards a pro-inflammatory phenotype. ApoA-I mimetic peptides including 4F have been investigated as potential anti-inflammatory therapies. I show that 4F targets the small intestine, where it is transported into the intestinal lumen in a cholesterol-dependent manner. In turn, 4F can increase trans-intestinal cholesterol efflux, a secondary cholesterol efflux pathways whose modulation is of therapeutic import. 4F therapy abrogates disease in the myeloid COX2 knock-out and cholate model of IBD, while rescuing the elevated levels of pro-inflammatory mediators in macrophages, intestinal tissue, and plasma. 4F can directly clear lipid pro-inflammatory mediators from tissue and plasma, strongly suggesting a causative role for changes in the levels of these mediator in both the protective mechanism of 4F and the pathogenic mechanism of COX2-mediated IBD. Further investigation into the protective mechanism of 4F identified a novel trans-intestinal lipid transport clearance pathway for inflammatory mediators, which pathway may be involved in 4F's protective mechanism. These findings are vivid examples of the synergy that can result from simultaneously investigating both pathogenic and protective mechanisms in genetic mouse models of disease.