Transected axons typically fail to regenerate in the central nervous system (CNS), resulting in chronic neurological disability in individuals with traumatic brain or spinal cord injury, glaucoma and ...ischemia-reperfusion injury of the eye. Although neuroinflammation is often depicted as detrimental, there is growing evidence that alternatively activated, reparative leukocyte subsets and their products can be deployed to improve neurological outcomes. In the current study, we identify a unique granulocyte subset, with characteristics of an immature neutrophil, that had neuroprotective properties and drove CNS axon regeneration in vivo, in part via secretion of a cocktail of growth factors. This pro-regenerative neutrophil promoted repair in the optic nerve and spinal cord, demonstrating its relevance across CNS compartments and neuronal populations. Our findings could ultimately lead to the development of new immunotherapies that reverse CNS damage and restore lost neurological function across a spectrum of diseases.
A major function of T helper (Th) 17 cells is to induce the production of factors that activate and mobilize neutrophils. Although Th17 cells have been implicated in the pathogenesis of multiple ...sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE), little attention has been focused on the role of granulocytes in those disorders. We show that neutrophils, as well as monocytes, expand in the bone marrow and accumulate in the circulation before the clinical onset of EAE, in response to systemic up-regulation of granulocyte colony-stimulating factor (G-CSF) and the ELR(+) CXC chemokine CXCL1. Neutrophils comprised a relatively high percentage of leukocytes infiltrating the central nervous system (CNS) early in disease development. G-CSF receptor deficiency and CXCL1 blockade suppressed myeloid cell accumulation in the blood and ameliorated the clinical course of mice that were injected with myelin-reactive Th17 cells. In relapsing MS patients, plasma levels of CXCL5, another ELR(+) CXC chemokine, were elevated during acute lesion formation. Systemic expression of CXCL1, CXCL5, and neutrophil elastase correlated with measures of MS lesion burden and clinical disability. Based on these results, we advocate that neutrophil-related molecules be further investigated as novel biomarkers and therapeutic targets in MS.
PURPOSE OF REVIEWThis review discusses concepts for diagnosing neuromyelitis optica spectrum disorders (NMOSD), distinguishing NMOSD from other inflammatory diseases of the central nervous system, ...and highlights recent and forthcoming data on acute and maintenance therapy of NMOSD.
RECENT FINDINGSThe neurologic manifestations of NMOSD are heterogenous, extending beyond classic presentations of optic neuritis and longitudinally extensive transverse myelitis. NMOSD may be comorbid with rheumatologic diseases, such as systemic lupus erythematosus, but is recognized as a distinct entity. Recent studies of acute treatment of NMOSD support early use of plasmapheresis. Relapse prevention is essential, as relapses can be disabling and patients may have only partial recovery. Current practice generally recommends at least 5 years of maintenance treatment. Recent randomized data demonstrates superiority of rituximab over azathioprine. Phase 3 trials have recently been completed or are underway studying novel therapies employing B-cell depletion, complement inhibition, and cell-based mechanisms (among other mechanisms) for maintenance therapy of NMOSD.
SUMMARYNMOSD is a heterogeneous but well-defined clinical entity, distinct from other neurologic and systemic inflammatory diseases, and treatment is poised for expansion.
Mature myeloid cells (macrophages and CD11b+ dendritic cells) form a prominent component of neuroinflammatory infiltrates in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). ...The mechanism by which these cells are replenished during relapsing and chronic neuroinflammation is poorly understood. Here we demonstrate that CD11b+CD62L+Ly6Chi monocytes with colony-forming potential are mobilized into the bloodstream by a granulocyte-macrophage colony-stimulating factor-dependent pathway immediately before EAE relapses. Circulating Ly6Chi monocytes traffic across the blood-brain barrier, up-regulate proinflammatory molecules, and differentiate into central nervous system dendritic cells and macrophages. Enrichment of Ly6Chi monocytes in the circulating pool is associated with an earlier onset and increased severity of clinical EAE. Our studies indicate that granulocyte-macrophage colony-stimulating factor–driven release of Ly6Chi precursors from the bone marrow prevents exhaustion of central nervous system myeloid populations during relapsing or chronic autoimmune demyelination, suggesting a novel pathway for therapeutic targeting.
Autoreactive CD4+ T cells, which target antigens in central nervous system (CNS) myelin, are widely believed to play a critical role in the pathogenesis of multiple sclerosis (MS) in concert with ...other immune effectors. This theory is supported by data from animal model experiments, genome-wide association studies, and immune profiles of individuals with MS. Furthermore, disease modifying agents that target lymphocytes significantly reduce the rate of MS clinical exacerbations. However, the properties of myelin-reactive CD4+ T cells that are critical for their pathogenic activities are not understood completely. This article reviews the literature on encephalitogenic CD4+ T cells, with an emphasis on T-helper (Th) lineage and cytokine production. An increased understanding of the spectrum of encephalitogenic T cells and how they differ from protective subsets is necessary for the development of the next generation of more effective and safer immunomodulatory therapies customized for individuals with MS and related disorders.
► Interleukin-23 polarized Th17 cells mediate autoimmune demyelinating disease. ► Th17 cells accumulate in the blood and central nervous system of individuals with MS. ► Paradoxically, ...encephalitogenicity is independent of IL-17 production. ► We discuss the putative mechanism of action of encephalitogenic Th17 cells.
It has been firmly established that IL-23 polarized T
H17 cells are potent effectors in the pathogenesis of experimental autoimmune encephalitomyelitis (EAE). However, the relative importance of these cells in comparison to other encephalitogenic T
H subsets, and the mechanisms that they employ to effect inflammatory demyelination, are topics of continuing investigation. Interestingly, deletion of individual ‘T
H17 cytokines’, such as IL-17A, IL-17F, IL-22 and IL-21, does not phenocopy the complete EAE-resistance of IL-23-deficient mice. The instability of T
H17 cells
in vivo introduces an additional layer of complexity to their role in the context of relapsing or chronic disease. Recent data indicate that IL-23 drives the production of myeloid activating factors, such as GM-CSF, by myelin-reactive T cells and facilitates their accumulation in the CNS. This review discusses the above issues in relation to the use of T
H17 cells and related factors as potential therapeutic targets and biomarkers in CNS autoimmune diseases such as multiple sclerosis (MS).
It has been firmly established that IL-23 polarized T(H)17 cells are potent effectors in the pathogenesis of experimental autoimmune encephalitomyelitis (EAE). However, the relative importance of ...these cells in comparison to other encephalitogenic T(H) subsets, and the mechanisms that they employ to effect inflammatory demyelination, are topics of continuing investigation. Interestingly, deletion of individual 'T(H)17 cytokines', such as IL-17A, IL-17F, IL-22 and IL-21, does not phenocopy the complete EAE-resistance of IL-23-deficient mice. The instability of T(H)17 cells in vivo introduces an additional layer of complexity to their role in the context of relapsing or chronic disease. Recent data indicate that IL-23 drives the production of myeloid activating factors, such as GM-CSF, by myelin-reactive T cells and facilitates their accumulation in the CNS. This review discusses the above issues in relation to the use of T(H)17 cells and related factors as potential therapeutic targets and biomarkers in CNS autoimmune diseases such as multiple sclerosis (MS).
A large body of data indicates that multiple sclerosis (MS) is an autoimmune disease which is initiated by CD4(+) T-helper 1 (Th1) and Th17 cells that are reactive against proteins in the myelin ...sheath. MS typically begins with a relapsing-remitting course, punctuated by clinical exacerbations associated with the development of focal inflammatory lesions in central nervous system white matter, followed by a secondary progressive (SP) phase, characterized by a gradual accumulation of neurological disability associated with widespread microglial activation and axonal loss. The molecular and cellular basis for this transition is unclear, and the role of inflammation during the SP stage is a subject of active debate. As of now, no immunological biomarkers have been identified in MS that are predictive of the clinical course or therapeutic responsiveness to disease-modifying agents, or that correlate with new lesion development, cumulative lesion load, or degree of disability. The discovery of such biomarkers would greatly facilitate clinical management and provide power for smaller and shorter clinical trials. In this article, we discuss the literature on immunological biomarkers in MS with a focus on stage-specific differences and similarities.
Innate immunity can facilitate nervous system regeneration, yet the underlying cellular and molecular mechanisms are not well understood. Here we show that intraocular injection of lipopolysaccharide ...(LPS), a bacterial cell wall component, or the fungal cell wall extract zymosan both lead to rapid and comparable intravitreal accumulation of blood-derived myeloid cells. However, when combined with retro-orbital optic nerve crush injury, lengthy growth of severed retinal ganglion cell (RGC) axons occurs only in zymosan-injected mice, and not in LPS-injected mice. In mice deficient for the pattern recognition receptor dectin-1 but not Toll-like receptor-2 ( TLR2 ), zymosan-mediated RGC regeneration is greatly reduced. The combined loss of dectin-1 and TLR2 completely blocks the proregenerative effects of zymosan. In the retina, dectin-1 is expressed by microglia and dendritic cells, but not by RGCs. Dectin-1 is also present on blood-derived myeloid cells that accumulate in the vitreous. Intraocular injection of the dectin-1 ligand curdlan a particulate form of β(1, 3)-glucan promotes optic nerve regeneration comparable to zymosan in WT mice, but not in dectin-1 ⁻/⁻ mice. Particulate β(1, 3)-glucan leads to increased Erk1/2 MAP-kinase signaling and cAMP response element-binding protein (CREB) activation in myeloid cells in vivo. Loss of the dectin-1 downstream effector caspase recruitment domain 9 (CARD9) blocks CREB activation and attenuates the axon-regenerative effects of β(1, 3)-glucan. Studies with dectin-1 ⁻/⁻/WT reciprocal bone marrow chimeric mice revealed a requirement for dectin-1 in both retina-resident immune cells and bone marrow-derived cells for β(1, 3)-glucan–elicited optic nerve regeneration. Collectively, these studies identify a molecular framework of how innate immunity enables repair of injured central nervous system neurons.
Significance Damage to neuronal networks in the central nervous system typically results in permanent functional deficits; however, the regenerative capacity of injured neurons can be dramatically augmented by local innate immune responses. Here we investigated the molecular and cellular events that participate in immune-mediated repair of severed optic nerve axons in the mouse. We show that intraocular administration of particulate β-glucan engages the immune receptor dectin-1 expressed on retina-resident microglia and infiltrating leukocytes, to trigger enhanced axonal regeneration. Delayed administration of β-glucan by two days is as effective as administration at the time of injury, suggesting a large therapeutic window. These data elucidate a new pathway of immune-mediated neural repair that may be targeted to reverse neurological disability.
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