Experimental Neuromyelitis Optica Induces a Type I Interferon Signature in the Spinal Cord.

Neuromyelitis optica (NMO) is an acute inflammatory disease of the central nervous system (CNS) which predominantly affects spinal cord and optic nerves. Most patients harbor pathogenic autoantibodies, the so-called NMO-IgGs, which are directed against the water channel aquaporin 4 (AQP4) on astrocytes. When these antibodies gain access to the CNS, they mediate astrocyte destruction by complement-dependent and by antibody-dependent cellular cytotoxicity. In contrast to multiple sclerosis (MS) patients who benefit from therapies involving type I interferons (I-IFN), NMO patients typically do not profit from such treatments. How is I-IFN involved in NMO pathogenesis? To address this question, we made gene expression profiles of spinal cords from Lewis rat models of experimental neuromyelitis optica (ENMO) and experimental autoimmune encephalomyelitis (EAE). We found an upregulation of I-IFN signature genes in EAE spinal cords, and a further upregulation of these genes in ENMO. To learn whether the local I-IFN signature is harmful or beneficial, we induced ENMO by transfer of CNS antigen-specific T cells and NMO-IgG, and treated the animals with I-IFN at the very onset of clinical symptoms, when the blood-brain barrier was open. With this treatment regimen, we could amplify possible effects of the I-IFN induced genes on the transmigration of infiltrating cells through the blood brain barrier, and on lesion formation and expansion, but could avoid effects of I-IFN on the differentiation of pathogenic T and B cells in the lymph nodes. We observed that I-IFN treated ENMO rats had spinal cord lesions with fewer T cells, macrophages/activated microglia and activated neutrophils, and less astrocyte damage than their vehicle treated counterparts, suggesting beneficial effects of I-IFN.

The "window of susceptibility" for inflammation in the immature central nervous system is characterized by a leaky blood-brain barrier and the local expression of inflammatory chemokines.

Early in postnatal development, the immature central nervous system (CNS) is more susceptible to inflammation than its adult counterpart. We show here that this "window of susceptibility" is characterized by the presence of leaky vessels in the CNS, and by a global chemokine expression profile which is clearly distinct from the one observed in the adult CNS and has three important characteristics. First, it contains chemokines with known roles in the differentiation and maturation of glia and neurons. Secondly, these chemokines have been described before in inflammatory lesions of the CNS, where they are important for the recruitment of monocytes and T cells. Lastly, the chemokine profile is shaped by pathological changes like oligodendrocyte stress and attempts of myelin repair. Changes in the chemokine expression profile along with a leaky blood-brain barrier pave the ground for an accelerated development of CNS inflammation.

The cholinergic anti-inflammatory system limits T cell infiltration into the neurodegenerative CNS, but cannot counteract complex CNS inflammation.

Stimulation of the nicotinic alpha7 acetylcholine receptor (nAChRalpha7) by nicotine or acetylcholine initiates the cholinergic anti-inflammatory pathway, a mechanism for neural inhibition of inflammation. The action of this pathway was initially discovered in animal models of endotoxemia and septic shock, and later described in a number of other diseases. Moreover, the action of this pathway is also implied in human degenerative diseases of the central nervous system (CNS) like amyotrophic lateral sclerosis or Alzheimer's disease. In spite of this general interest, little is known about its involvement in regulating T cell entry into, or inflammatory reactions within the CNS. We tested the action of the cholinergic anti-inflammatory pathway in nAChRalpha7-deficient mice and their wildtype counterparts in two different experimental settings: In the facial nerve axotomy model characterized by neurodegeneration and T cell infiltration, and in the experimental autoimmune encephalomyelitis (EAE) model providing a very complex scenario of CNS inflammation and demyelination. We found that the cholinergic anti-inflammatory pathway limits the site-directed influx of activated T cells into the lesioned facial motor nucleus, but cannot counteract CNS inflammation in EAE.

After injection into the striatum, in vitro-differentiated microglia- and bone marrow-derived dendritic cells can leave the central nervous system via the blood stream.

The prototypic migratory trail of tissue-resident dendritic cells (DCs) is via lymphatic drainage. Since the central nervous system (CNS) lacks classical lymphatic vessels, and antigens and cells injected into both the CNS and cerebrospinal fluid have been found in deep cervical lymph nodes, it was thought that CNS-derived DCs exclusively used the cerebrospinal fluid pathway to exit from tissues. It has become evident, however, that DCs found in peripheral organs can also leave tissues via the blood stream. To study whether DCs derived from microglia and bone marrow can also use this route of emigration from the CNS, we performed a series of experiments in which we injected genetically labeled DCs into the striata of rats. We show here that these cells migrated from the injection site to the perivascular space, integrated into the endothelial lining of the CNS vasculature, and were then present in the lumen of CNS blood vessels days after the injection. Moreover, we also found these cells in both mesenteric lymph nodes and spleens. Hence, microglia- and bone marrow-derived DCs can leave the CNS via the blood stream.