Myelin alters the inflammatory phenotype of macrophages by activating PPARs

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.

Scavenger receptor collectin placenta 1 is a novel receptor involved in the uptake of myelin by phagocytes

“…Previously, we found that myelin-derived lipids, such as cholesterol metabolites and fatty acids, partially account for the phenotype of phagocytes after myelin uptake418. Activation of the liver X receptor (LXR) and peroxisome proliferator-activated receptor β/δ (PPARβ/δ) underlies the impact of these lipids on the phenotype of phagocytes.…”

Solubilized extracellular matrix from brain and urinary bladder elicits distinct functional and phenotypic responses in macrophages

“…This hypothesis could account for the inflammatory activity of B-ECM as low molecular weight HA has been shown to be inflammatory while high molecular weight has been shown to be anti-inflammatory [36,83,84]. Additional proteoglycans such as myelin, which is abundant in brain ECM, have also been shown to be inflammatory at low molecular weight [34,37]. As HA has been shown to differentially regulate the inflammatory response depending on the molecular weight, solubilized U-ECM was further digested with hyaluronidase to determine if the HA molecules in the solubilized U-ECM play a role in the observed macrophage response (i.e., high PGE2 and low proinflammatory factor secretion).…”

Myelin as an inflammatory mediator: Myelin interactions with complement, macrophages, and microglia in spinal cord injury

“…First, in several of these in vitro paradigms, researchers load macrophages with myelin prior to applying inflammatory stimuli. In response to proinflammatory stimuli, these myelin‐laden macrophages almost invariably express anti‐inflammatory mediators and/or stop responding to the proinflammatory stimuli (Bogie et al, , ; Boven et al, ). Second, myelin stimulation in isolation invokes either no phenotypic activation or causes release of ROS and proinflammatory cytokines, with a few reports of subtle M2‐like activation in a cell type–specific manner (Kroner et al, ; Sun et al, ; van der Laan et al, ; van Rossum, Hilbert, Straßenburg, Hanisch, & Brück, ; Wang et al, ; Williams et al, ).…”