Third Prize MAI AWARD Winner PRO-RESOLVING LIPID MEDIATORS IN THE RESOLUTION OF MULTIPLE SCLEROSIS: NOVEL PATHOGENIC IMPLICATIONS FOR AUTOIMMUNITY AND NEUROINFLAMMATION
- Valerio Chiurchiu, Italy
Abstract
Background and Aims
Chronic neuroinflammation and autoimmunity are key pathological hallmarks of multiple sclerosis (MS) and entail a dysregulation of the natural process to resolve inflammation which is orchestrated by the super-family of specialized pro-resolving mediators (SPMs), that include lipoxins (LXs), resolvins (Rvs), protectins (PDs) and maresins (MaRs), that have been shown to modulate critical subsets of autoreactive T cells. Yet the role of resolution of inflammation in multiple sclerosis is still unknown.
Methods
We performed targeted-metabololipidomics in the plasma of healthy donors and MS patients with different clinical forms of disease and we analyzed the expression of SPM biosynthetic enzymes and receptors in leukocytes obtained from MS patients. Furthermore, we investigated the response of key pathogenic cells involved in MS to specifically altered SPMs by means polychromatic flow cytometry and using a primary model of blood brain barrier.
Results
We identified a unique lipid mediator signature associated with MS clinical forms and we reported an impaired plasma production of specific SPMs (e.g. RvD1 and PD1), which were strongly reduced along disease progression. These findings were supported by impaired/altered expression of key SPM biosynthetic enzymes and receptors (e.g. 15-LOX, GRP32, GRP18) in leukocytes of MS patients. Furthermore, RvD1 and PD1 reduced activation and cytokine production from monocytes of MS patients and inhibited inflammation-induced blood-brain barrier dysfunction.
Conclusions
Overall, we here provide critical evidence of a failed resolution pathway within the neuro-immune axis in MS, suggesting new insights into its autoimmune pathogenesis and providing innovative diagnostic and therapeutic approaches.