Abstract
BackgroundMacrophages play a dual role in multiple sclerosis (MS) pathology. They can exert neuroprotective and growth promoting effects but also contribute to tissue damage by production of inflammatory mediators. The effector function of macrophages is determined by the way they are activated. Stimulation of monocyte-derived macrophages in vitro with interferon-γ and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages.MethodsFor this study, the expression of a panel of typical M1 and M2 markers on human monocyte derived M1 and M2 macrophages was analyzed using flow cytometry. This revealed that CD40 and mannose receptor (MR) were the most distinctive markers for human M1 and M2 macrophages, respectively. Using a panel of M1 and M2 markers we next examined the activation status of macrophages/microglia in MS lesions, normal appearing white matter and healthy control samples.ResultsOur data show that M1 markers, including CD40, CD86, CD64 and CD32 were abundantly expressed by microglia in normal appearing white matter and by activated microglia and macrophages throughout active demyelinating MS lesions. M2 markers, such as MR and CD163 were expressed by myelin-laden macrophages in active lesions and perivascular macrophages. Double staining with anti-CD40 and anti-MR revealed that approximately 70% of the CD40-positive macrophages in MS lesions also expressed MR, indicating that the majority of infiltrating macrophages and activated microglial cells display an intermediate activation status.ConclusionsOur findings show that, although macrophages in active MS lesions predominantly display M1 characteristics, a major subset of macrophages have an intermediate activation status.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS)
Our findings indicate that foamy macrophages in active demyelinating multiple sclerosis (MS) lesions display an intermediate activation status supporting the idea that in vitro polarization of macrophages and microglia cannot be translated to pathology of diseased tissues in vivo
Expression of M1 and M2 markers on in vitro generated macrophages Peripheral blood mononuclear cell (PBMC) were obtained from three different donors and cultured for 7 days to mature into macrophages, stimulated with either IL-4 (M2) or IFN-γ and LPS (M1) or left unstimulated (M0)
Summary
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS). It is the most common cause of neurological disability among young adults, affecting approximately one in 1,000 individuals in Europe and North America [1]. Many lines of evidence indicate that macrophages play a dual role in the pathogenesis of MS as they contribute to lesion formation and axonal damage, and support repair mechanisms [4,5]. Macrophages play a dual role in multiple sclerosis (MS) pathology They can exert neuroprotective and growth promoting effects and contribute to tissue damage by production of inflammatory mediators. Stimulation of monocyte-derived macrophages in vitro with interferon-γ and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages
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