The immunomodulatory effects of phosphatidylserine containing liposomes in EAE rats

Abstract

Multiple Sclerosis is an autoimmune disease, characterized by chronic inflammation and demyelination in the central nervous system (CNS). Macrophages play a central role in the disease process of MS and its animal model experimental autoimmune encephalomyelitis (EAE) by phagocytizing myelin and releasing inflammatory and toxic mediators in the CNS. Although tradiionally regarded to be detrimental, it was recently demonstrated that myelin-laden macrophages present in MS and EAE lesions seem to exert an anti-inflammatory 'M2'-phenotype. However, it is still not completely clear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can affect lesion progression. Research at Biomed identified phosphatidylserine (PS), a phospholipid abundantly present in myelin that can induce an anti-inflammatory phenotype in macrophages. We therefore investigated the impact of PS-liposomes (PSLs) on the functional phenotype of macrophages in vitro and in vivo during EAE. We hypothesized that phosphatidylserine containing liposomes will ameliorate chronic EAE in rats through the polarization of macrophages into an anti-inflammatory phenotype. In summary, this study shows that PSLs alter the functional properties of macrophages in vitro by activating PPAR-β/δ and PPAR-α. Moreover, systemic treatment of PSLs had both a prophylactic and therapeutic effect on EAE, which was paralleled by a reduced splenic lymphocyte proliferation, less CNS cell trafficking, a reduction in size of splenic follicles, and a decreased secretion of inflammatory mediators in the spleen. More importantly, the homing of PSLs to splenic macrophages following intravenous injections and the subsequent change in expression of TNF-α, iNOS, OPN and Arg-1, illustrates a crucial role for a PSLmediated activation of PPAR-β/δ and PPAR-α in macrophages in the observed effects on EAE. Additionally, activation of PPAR-β/δ and possibly PPAR-α seems to be dependent on the composition and distribution of fatty acid chains in phosphatidylserine. The results of our study suggest that increased apoptotic signals introduced by PSLs can promote an antiinflammatory environment, and may encourage a further in vivo evaluation of PSLs regarding their potential therapeutic effect on inflammatory responses. Current therapies for MS partially reduce new lesion development and prevent clinical disease activity to a certain degree, but none can halt the progression or cure the disease. Expanding on the knowledge of PSLs, identification of anti-inflammatory constituents can lead to a new therapeutic approach, with the goal of inducing repair mechanisms in MS.