Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics.

There are over 15 disease-modifying drugs that have been approved over the last 20 years for the treatment of relapsing-remitting multiple sclerosis (MS), but there are limited treatment options available for progressive MS. The development of new drugs for the treatment of progressive MS remains challenging as the pathophysiology of progressive MS is poorly understood.The progressive phase of MS is dominated by neurodegeneration and a heightened innate immune response with trapped immune cells behind a closed blood-brain barrier in the central nervous system. Here we review microglia and border-associated macrophages, which include perivascular, meningeal, and choroid plexus macrophages, during the progressive phase of MS. These cells are vital and are largely the basis to define lesion types in MS. We will review the evidence that reactive microglia and macrophages upregulate pro-inflammatory genes and downregulate homeostatic genes, that may promote neurodegeneration in progressive MS. We will also review the factors that regulate microglia and macrophage function during progressive MS, as well as potential toxic functions of these cells. Disease-modifying drugs that solely target microglia and macrophage in progressive MS are lacking. The recent treatment successes for progressive MS include include B-cell depletion therapies and sphingosine-1-phosphate receptor modulators. We will describe several therapies being evaluated as a potential treatment option for progressive MS, such as immunomodulatory therapies that can target myeloid cells or as a potential neuroprotective agent.

Elevated levels of serum CD5 antigen-like protein distinguish secondary progressive multiple sclerosis from other disease subtypes.

CD5 antigen-like (CD5L) protein is a macrophage-secreted protein with roles in immunomodulation and lipid homeostasis. We compared serum CD5L levels in healthy controls to individuals diagnosed with clinically isolated syndrome, relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP) multiple sclerosis (MS). CD5L was increased in SPMS relative to controls, RRMS, and PPMS. SPMS CD5L was associated with longer disease duration independent of age, sex, or disease severity. The positive relationship between CD5L and disease duration in SPMS suggests a chronic peripheral inflammatory profile compared to other subtypes, particularly PPMS, warranting investigation of functional roles for CD5L in MS.

Mucosal Administration of E-selectin Limits Disability in Models of Multiple Sclerosis.

E-selectin plays an important role in mediating the rolling of leukocytes along and thus, the subsequent extravasation across activated endothelial cells comprising the microvasculature of the blood brain barrier (BBB). In multiple sclerosis (MS) and other inflammatory disorders of the central nervous system (CNS), the microvasculature is altered and immune cells infiltrate the brain and spinal cord contributing to damage, demyelination and ultimately disability. While mucosal administration is typically used to affect lymphocyte hyporesponsiveness or tolerance to suspect autoantigens, intranasal administration to E-selectin has previously been shown to protect against CNS inflammatory insults. We characterized the potential for mucosal administration of E-selectin to modulate CNS autoimmunity in the experimental autoimmune encephalomyelitis (EAE) model of MS. Intranasally administered E-selectin reduced swelling by as much as 50% in delayed-type hypersensitivity reactions compared to ovalbumin-tolerized controls. Intranasal E-selectin delivery prior to disease induction with myelin oligodendrocyte glycoprotein (MOG)35-55 reduced disease severity and total disease burden by more than 50% compared to PBS-tolerized animals; this protection was not associated with differences in the magnitude of the autoimmune response. Examination after the onset of disease showed that protection was associated with significant reductions in inflammatory infiltrates throughout the spinal cord. Tolerization to E-selectin did not influence encephalitogenic characteristics of autoreactive T cells such as IFN-gamma or IL-17 production. Clinical disease was also significantly reduced when E-selectin was first delivered after the onset of clinical symptoms. Splenic and lymph node (LN) populations from E-selectin-tolerized animals showed E-selectin-specific T cell responses and production of the immunomodulatory cytokine IL-10. Transfer of enriched CD4+ T cells from E-selectin tolerized mice limited disability in the passive SJL model of relapsing remitting MS. These results suggest a role for influencing E-selectin specific responses to limit neuroinflammation that warrants further exploration and characterization to better understand its potential to mitigate neurodegeneration in disorders such as MS.