Myelin alters the inflammatory phenotype of macrophages by activating PPARs

Jeroen Fj Bogie,Piet Stinissen,Noam Zelcer,Jerome Ja Hendriks,Philip G Nijland,Winde Jorissen,Niels Hellings,Jack Van Horssen,Jo Mailleux,Tim Vanmierlo

doi:10.1186/2051-5960-1-43

Abstract

BackgroundFoamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions. Recent studies have described an altered phenotype of macrophages after myelin internalization. However, mechanisms by which myelin affects the phenotype of macrophages and how this phenotype influences lesion progression remain unclear.ResultsWe demonstrate that myelin as well as phosphatidylserine (PS), a phospholipid found in myelin, reduce nitric oxide production by macrophages through activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). Furthermore, uptake of PS by macrophages, after intravenous injection of PS-containing liposomes (PSLs), suppresses the production of inflammatory mediators and ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The protective effect of PSLs in EAE animals is associated with a reduced immune cell infiltration into the central nervous system and decreased splenic cognate antigen specific proliferation. Interestingly, PPARβ/δ is activated in foamy macrophages in active MS lesions, indicating that myelin also activates PPARβ/δ in macrophages in the human brain.ConclusionOur data show that myelin modulates the phenotype of macrophages by PPAR activation, which may subsequently dampen MS lesion progression. Moreover, our results suggest that myelin-derived PS mediates PPARβ/δ activation in macrophages after myelin uptake. The immunoregulatory impact of naturally-occurring myelin lipids may hold promise for future MS therapeutics.

Highlights

Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions
Myelin and PS modulate the macrophages phenotype by activating peroxisome proliferator-activated receptor (PPAR) To assess whether myelin affects the inflammatory phenotype of macrophages through activation of PPARα, β/δ or γ, macrophages were treated for 2 h with specific antagonists for PPARα (GW6471), β/δ (GSK0660) and γ (GW9662), prior to administration of myelin
The peroxisome proliferator-activated receptor β/δ (PPARβ/δ) antagonist did not affect the capacity of macrophages to internalize myelin or liposomes (Additional file 1: Figure S1e-g), indicating that a reduced internalization of myelin and liposomes does not account for the increase in nitric oxide (NO) production following administration of the PPARβ/δ antagonist

Summary

Introduction

Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions. Apoptotic cell clearance via PS skews macrophages and microglia towards an anti-inflammatory phenotype, similar to myelin-phagocytosing macrophages, hereby suppressing inflammation and maintaining homeostasis [21,22,23,24]. We demonstrate that myelin as well as PS suppress the production of the inflammatory mediator nitric oxide (NO) by macrophages through activation of PPARβ/δ. We provide compelling evidence that PSLs are immunosuppressive in an experimental MS animal model and that PPARβ/δ responsive genes and their corresponding proteins are markedly upregulated in myelin-phagocytosing macrophages in active demyelinating MS lesions.

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