ECCO 2016: Mechanisms by which inflammation resolves
Silvio Danese, Humanitas Clinical and Research Hospital, Milan, Italy.
Article by Maria Dalby – The current paradigm for managing inflammatory conditions is to suppress the inflammatory response by targeting pro-inflammatory mediators. However, like any well-orchestrated defence mechanism, the acute inflammatory response contains the mechanisms of its resolution – mechanisms for removing dead cells and debris, switching of survival signals and normalising chemokine gradients, and draining inflammatory exudates via lymphatic vessels – and boosting these mechanisms may offer a new and more effective target for combatting chronic inflammation. Professor Silvio Danese from Milan presented an overview of this pioneering field of research.
In normal inflammation the onset phase is usually a balanced response which is resolved without any long-lasting damage. In contrast, chronic inflammation occurs when the onset phase involves an excessive response which fails to resolve and leads to tissue destruction.1 Just as inflammation has its cardinal signs of fever, erythema, oedema, pain and loss of function, five cardinal signs of resolution have been described in the literature: removal of microbes, dead cells and debris; restoration of vascular integrity and perfusion; regeneration of tissue; remission of fever; and relief of pain.2 One of the most up-to-the-minute research topics in IBD at the moment is to understand the underlying mechanisms of these signs and identify critical mediators that could provide potential targets for pharmacological intervention with pro-resolving agents.3Researchers at Professor Danese’s centre have found that the main pro-resolving mediator molecules derived from omega-6 (arachidonic acid; AA) and omega-3 (docosahexaenoic acid; DHA) fatty acids are downregulated in UC patients with active disease. The key to this downregulation may be a deficient uptake mechanism in endothelial cells; the MFSD2A transporter has been shown to facilitate uptake of DHA across the blood-brain endothelial barrier to resolve brain inflammation.4 Professor Danese’s group have shown that MFSD2A is expressed by intestinal endothelium and that over-expression of MFSD2A inhibits NF-κB signalling via the peroxisome proliferator-activated receptor (PPAR) gamma and blocks the expression of pro-inflammatory markers. MFSD2A expression is dysfunctional in the mucosa during active inflammation – what remains to be shown is whether restoring MFSD2A expression has a beneficial effect on the inflammation.
Another important hunting ground for pro-resolving targets is the lymphatic circulation in the gut.5 Defective lymphatic function is a feature of both CD and UC; experimental data shows that restoring function using the prolymphangiogenic vascular endothelial growth factor (VEGF)-C can resolve dextran sulfate sodium (DSS)-induced colitis in mice.6Professor Danese concluded his talk by stressing that this field of research is as yet in its infancy and that a host of other potential targets may be available and offer an opportunity for developing innovative pro-resolving drugs.1 One example of a pro-resolving drug that is already in clinical development for the treatment of IBD is oral SMAD7 antisense oligonucleotide mongersen which acts by inhibiting TGF-β1 signaling7 and has been shown to be superior to placebo for inducing a clinical response and remission in patients with active CD.8
- Perretti M, Leroy X, Bland EJ, et al. Resolution Pharmacology: Opportunities for Therapeutic Innovation in Inflammation. Trends Pharmacol Sci 2015;36:737-55.
- Basil MC, Levy BD. Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Nat Rev Immunol 2016;16:51-67.
- Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol 2014;14:329-42.
- Nguyen LN, Ma D, Shui G, et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature 2014;509:503-6.
- Danese S. Role of the vascular and lymphatic endothelium in the pathogenesis of inflammatory bowel disease: ‘brothers in arms’. Gut 2011;60:998-1008.
- D’Alessio S, Correale C, Tacconi C, et al. VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J Clin Invest 2014;124:3863-78.
- Fiocchi C. TGF-beta/Smad signaling defects in inflammatory bowel disease: mechanisms and possible novel therapies for chronic inflammation. J Clin Invest 2001;108:523-6.
- Monteleone G, Neurath MF, Ardizzone S, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N Engl J Med 2015;372:1104-13.