Myeloid cell plasticity in the evolution of central nervous system autoimmunity

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Myeloid cells, including macrophages (MΦs) and dendritic cells (DCs), are a major component of white matter lesions in multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE).1 Our laboratory and others have established a critical role of myeloid cells in early EAE pathogenesis.3 Myeloid cells may serve as antigen‐presenting cells for reactivation of myelin‐specific CD4+ T cells,7 secrete cytokines such as IL‐6, IL‐1β, and TNFα,9 and directly inflict damage through release of toxic factors such as reactive oxygen species generated by inducible nitric oxide synthase (iNOS).10 iNOS‐expressing myeloid cells are often described as classically activated, and considered “proinflammatory,” based on their similarity to bone marrow–derived macrophages (BMDMs) that were polarized with lipopolysaccharide or interferon‐γ (IFNγ) in vitro.12 It is generally thought that classically activated myeloid cells (CAMCs) are predominant in active MS and EAE lesions, where they act as pathogenic effector cells.13 Early studies of autopsied MS brains revealed iNOS‐immunoreactive macrophages in active lesions.14 The presence of iNOS+ myeloid cells generally correlated with zones of ongoing demyelination.
However, there is growing evidence that myeloid cells that accumulate in the central nervous system (CNS) are heterogeneous and likely encompass a spectrum of lineages with diverse, and even opposing, properties.18 In contrast to iNOS, the enzyme arginase‐1 (Arg1) and the mannose receptor (CD206) have been identified as markers of myeloid cells with “immunosuppressive” or “proregenerative” properties. Arg1/CD206‐expressing myeloid cells play a critical role in wound healing.21 They are frequently classified as alternatively activated based on their similarity to BMDMs generated in vitro by polarization with IL‐4 or IL‐13 via a STAT6‐dependent pathway.12 Alternatively activated myeloid cells (AAMCs) may regulate the inflammatory environment by secreting IL‐10 and/or TGFβ1,9 while promoting tissue regeneration by clearing debris23 and secreting growth factors.25 Foamy (lipid‐laden) macrophages, perivascular macrophages, and microglia expressing human AAMC markers, such as CD206 and CD163, have been discovered in acute and chronic active MS lesions.2 Primary human macrophages acquire a foamy morphology and produce immunosuppressive factors following ingestion of myelin in vitro.19
We questioned whether CNS myeloid cells evolve during disease progression and shift from a proinflammatory phenotype at onset to a noninflammatory or immunosuppressive state in anticipation of clinical remission/stabilization. Consistent with this hypothesis, CNS‐infiltrating DCs were found to upregulate the AAMC‐associated genes Arg1, Chi3l3, and Ms4a8a at the peak of EAE, shortly prior to remission.27 Arg1 is the most significantly upregulated gene in the CNS at peak EAE.28 Adoptive transfer of AAMC‐polarized macrophages or microglia can ameliorate EAE,29 and the therapeutic effects of estrogen, glatiramer acetate, and other agents in EAE were found to correlate with the expansion of AAMCs in the periphery and/or CNS.31 Less is known about endogenous AAMCs that spontaneously accumulate in the CNS during the course of EAE or MS. In the current paper, we compare the spatial distribution of AAMCs in actively demyelinating and quiescent regions of MS lesions. In addition, we examine the origin, kinetics, and biological properties of CNS myeloid subsets from the preclinical stage of EAE through peak and remission.
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