T(H)17 lymphocytes appear to be essential in the pathogenesis of numerous inflammatory diseases. We demonstrate here the expression of IL-17 and IL-22 receptors on blood-brain barrier endothelial cells (BBB-ECs) in multiple sclerosis lesions, and show that IL-17 and IL-22 disrupt BBB tight junctions in vitro and in vivo. Furthermore, T(H)17 lymphocytes transmigrate efficiently across BBB-ECs, highly express granzyme B, kill human neurons and promote central nervous system inflammation through CD4+ lymphocyte recruitment.
The specific signals mediating the activation of microglia and astrocytes as a prelude to, or consequence of, CNS inflammation continue to be defined. We investigated TLRs as novel receptors mediating innate immune responses in human glial cells. We find that microglia express mRNA for TLRs 1–9, whereas astrocytes express robust TLR3, low-level TLR 1, 4, 5, and 9, and rare-to-undetectable TLR 2, 6, 7, 8, and 10 mRNA (quantitative real-time PCR). We focused on TLRs 3 and 4, which can signal through both the MyD88-dependent and -independent pathways, and on the MyD88-restricted TLR2. By flow cytometry, we established that microglia strongly express cell surface TLR2; TLR3 is expressed at higher levels intracellularly. Astrocytes express both cell surface and intracellular TLR3. All three TLRs trigger microglial activation upon ligation. TLR3 signaling induces the strongest proinflammatory polarizing response, characterized by secretion of high levels of IL-12, TNF-α, IL-6, CXCL-10, and IL-10, and the expression of IFN-β. CXCL-10 and IL-10 secretion following TLR4 ligation are comparable to that of TLR3; however, other responses were lower or absent. TLR2-mediated responses are dominated by IL-6 and IL-10 secretion. Astrocytes respond to TLR3 ligation, producing IL-6, CXCL-10, and IFN-β, implicating these cells as contributors to proinflammatory responses. Initial TLR-mediated glial activation also regulates consequent TLR expression; while TLR2 and TLR3 are subject to positive feedback, TLR4 is down-regulated in microglia. Astrocytes up-regulate all three TLRs following TLR3 ligation. Our data indicate that activation of innate immune responses in the CNS is not homogeneous but rather tailored according to cell type and environmental signal.
Multiple sclerosis (MS) is a central nervous system (CNS) disease characterized by patches of demyelination and infiltration of inflammatory cells (21). The etiology of this disabling diseasehas not yet been determined, but both genetic factors, such as genes encoding human leukocyte antigens, T-cell receptors, and myelin basic protein (MBP) (18,19,26), and environmental factors such as viruses have been implicated (31). At least four human demyelinating diseases have a known viral etiology: subacute sclerosing panencephalitis as a late complication of measles virus infection of childhood (35), progressive multifocal leukoencephalopathy caused by the JC papovavirus (57), encephalopathy and myelopathy (neuro-AIDS) caused by human immunodeficiency virus (43), and human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (28). Over the last decades, several viruses have been associated with MS, based on detection of virions, viral nucleic acids, or viral proteins in CNS or the presence of antiviral antibodies in serum and/or cerebrospinal fluid. A confirmed association with MS is awaited but may involve more than one virus.Several studies have associated human coronaviruses (HCoV) with MS. Coronavirus-like particles were detected in autopsied brain tissue from an MS patient (56). Two coronaviruses that are molecularly related to murine neurotropic coronaviruses were isolated from brain material obtained at autopsy from two MS patients (9). Intrathecal anti-HCoV antibody synthesis indicative of a CNS infection was reported in MS patients (45). HCoV RNA was detected in MS patient brains (37, 51) and in cerebrospinal fluid of MS and other neurological disease (OND) patients (15). Coronavirus antigens were also detected in MS patient brains (37). Moreover, we have shown that HCoV can infect human astrocytes and microglia in primary cultures (8) and can acutely and persistently infect immortalized human glial cells (4, 5). Thus, accumulating evidence suggests that these viruses, first isolated as pathogens of the respiratory tract and now associated with up to one-third of human common colds (39), might be neurotropic, neuroinvasive, and neurovirulent in humans, as is the case for their murine counterpart, the coronavirus mouse hepatitis virus (MHV). Interestingly, upper respiratory infections of viral origin were shown to be an important trigger of MS attacks (2,40,48). Moreover, coronavirus seasonal patterns fit the observed occurrence of MS exacerbations (48).MHV-induced demyelinating disease involving coronaviruses is used as an animal model for elucidating the complex pathogenesis of MS. As for MS, MHV pathogenesis is multifactorial (27). Its outcome is influenced by genetics of the host and virus, dose and route of inoculation, and host age and immunological status at the time of infection (58). Neurotropic MHV strains could invade the CNS following an intranasal inoculation in mice (34) and could also gain access to the CNS via the hematogenous and/or lymphatic systems in mice (7) and i...
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