The chemokine receptor CCR5 in the central nervous system

The expression and the role of the chemokine receptor CCR5 have been mainly studied in the context of HIV infection. However, this protein is also expressed in the brain, where it can be crucial in determining the outcome in response to different insults. CCR5 expression can be deleterious or protective in controlling the progression of certain infections in the CNS, but it is also emerging that it could play a role in non-infectious diseases. In particular, it appears that, in addition to modulating immune responses, CCR5 can influence neuronal survival. Here, we summarize the present knowledge about the expression of CCR5 in the brain and highlight recent findings suggesting its possible involvement in neuroprotective mechanisms.     

HHV-8/KSHV is not associated with AIDS-related primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a major complication of the late stages of human immunodeficiency virus (HIV) disease. Epstein Barr virus (EBV) infection is the only genetic lesion consistently associated with this neoplasia. Recently, it has been proposed that the pathogenesis of AIDS-related PCNSL (AIDS-PCNSL) may be associated with infection by human herpesvirus-8/Kaposi's sarcoma associated herpesvirus (HHV-8/KSHV), although at present such association remains controversial. In order to conclusively assess the link between HHV-8/KSHV infection and AIDS-PCNSL, we performed a comprehensive study based on multiple molecular assays on cerebral tissues and cerebrospinal fluid (CSF) as well as specific immunologic assays on patients' sera. A well characterized panel of 33 Italian patients with AIDS-PCNSL and 13 controls with other HIV-related brain focal diseases from the same geographical area was analyzed. No signs of HHV-8/KSHV infection were detected in cerebral tissues by single-step PCR. Cerebral tissues of all AIDS-PCNSL scored negative for HHV-8/KSHV DNA sequences also by nested PCR, with the exception of one single patient who was simultaneously affected by Kaposi's sarcoma. All CSF samples analyzed were consistently devoid of HHV-8/KSHV sequences by molecular assays. By serologic assays, detecting both latent and lytic HHV-8/KSHV antigens, a specific immunoreactivity was observed in 16/33 (48%) AIDS-PCNSL and in 6/13 (46%) controls (P = 0.88). A significant correlation with HHV-8/KSHV serum reactivity was seen with a homosexual route of HIV transmission (P = 0.018), but not with the presence of AIDS-PCNSL. The results of our analysis conclusively assess that HHV-8/KSHV infection is not a feature of AIDS-PCNSL.     

Aging is associated with increased human T cell CC chemokine receptor gene expression.

Leukocyte chemokine receptors (CR) are central to the pathogenesis of many human diseases, including human immunodeficiency virus-1 (HIV-1) infection. Elderly individuals infected with the HIV-1 virus have a shorter disease-free interval and worse clinic outcome. However, the reasons for this are unclear. We recently reported increased CC chemokine receptor (CCR) expression in CD4+ T cells in aged mice, but it is not known if similar changes occur in humans. In addition, it is unclear if the observed differences are related to aged-related expansion in the memory T cell compartment. In this report, we examined the effects of aging on CCR gene expression in human peripheral blood mononuclear cells (PBMCs), CD4+ T cells, and naive/memory T cells. Aging is found to be associated with increased CCR1-5 expression in PBMCs and CD4+ T cells. In addition, although the age-related increases in CCR expression occurred in both naive and memory T cells, the greatest changes were seen in the memory T cell subset. We propose that the observed aging-associated increase in T cell chemokine receptor expression may contribute to the worse clinical outcome of T cell chemokine receptor-dependent disease, such as HIV-1 infection, in the elderly.     

Functional analysis of the CC chemokine receptor 5 (CCR5) on virus-specific CD8+ T cells following coronavirus infection of the central nervous system

Intracranial infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a demyelinating disease similar in pathology to the human disease multiple sclerosis (MS). T cells participate in both defense and disease progression following MHV infection. Expression of chemokine receptors on activated T cells is important in allowing these cells to traffic into and accumulate within the central nervous system (CNS) of MHV-infected mice. The present study evaluated the contributions of CCR5 to the activation and trafficking of virus-specific CD8(+) T cells into the MHV-infected CNS mice. Comparable numbers of virus-specific CD8(+) T cells derived from immunized CCR5(+/+) or CCR5(-/-) mice were present within the CNS of MHV-infected RAG1(-/-) mice following adoptive transfer, indicating that CCR5 is not required for trafficking of these cells into the CNS. RAG1(-/-) recipients of CCR5(-/-)-derived CD8(+) T cells exhibited a modest, yet significant (P 相似文献   

C10 is a novel chemokine expressed in experimental inflammatory demyelinating disorders that promotes recruitment of macrophages to the central nervous system

Chemokines may be important in the control of leukocytosis in inflammatory disorders of the central nervous system. We studied cerebral chemokine expression during the evolution of diverse neuroinflammatory disorders in transgenic mice with astrocyte glial fibrillary acidic protein-targeted expression of the cytokines IL-3, IL-6, or IFN-alpha and in mice with experimental autoimmune encephalomyelitis. Distinct chemokine gene expression patterns were observed in the different central nervous system inflammatory models that may determine the phenotype and perhaps the functions of the leukocytes that traffic into the brain. Notably, high expression of C10 and C10-related genes was found in the cerebellum and spinal cord of GFAP-IL3 mice with inflammatory demyelinating disease and in mice with experimental autoimmune encephalomyelitis. In both these neuroinflammatory models, C10 RNA and protein expressing cells were predominantly macrophage/microglia and foamy macrophages present within demyelinating lesions as well as in perivascular infiltrates and meninges. Intracerebroventricular injection of recombinant C10 protein promoted the recruitment of large numbers of Mac-1(+) cells and, to a much lesser extent, CD4(+) lymphocytes into the meninges, choroid plexus, ventricles, and parenchyma of the brain. Thus, C10 is a prominent chemokine expressed in the central nervous system in experimental inflammatory demyelinating disease that, we show, also acts as a potent chemotactic factor for the migration of these leukocytes to the brain.     

Cytokine and chemokine expression in the central nervous system associated with protective cell-mediated immunity against Cryptococcus neoformans.

Cryptococcus neoformans is a yeast that causes cryptococcosis, a life-threatening disease that develops following inhalation and dissemination of the organisms. C. neoformans has a predilection for the central nervous system (CNS) and mortality is most frequently associated with meningoencephalitis. Susceptibility to cryptococcosis is increased in patients with deficiencies in cell-mediated immunity (CMI). Because cryptococcal CNS infections are associated with mortality and diagnosis of cryptococcosis is often not made until after dissemination to the CNS, a better understanding of host defense mechanisms against C. neoformans in the CNS is needed to design improved therapies for immunocompromised individuals suffering from cryptococcosis. Using a mouse model, we previously described a protective cell-mediated immune response induced in the periphery that limited the growth of C. neoformans in the CNS. In the current investigation, we examined cytokine and chemokine expression in the CNS to identify factors important in achieving protective immunity. We observed increased expression of IL-1beta, TNF-alpha, IFN-gamma, MCP-1, RANTES, and IP-10 in C. neoformans-infected brains of immune mice compared to control mice suggesting that these cytokines and chemokines are associated with the protective immune response. Furthermore, the Th1-type cytokines TNF-alpha and IFN-gamma, but not the Th2 cytokines IL-4 and IL-5, were secreted at significantly higher levels in C. neoformans-infected brains of immune mice compared to control mice. Our results demonstrate that cytokines and chemokines associated with CMI are produced following infection in the CNS of immunized mice, and the expression of these factors correlates with protection against C. neoformans in the CNS.     

Differential recruitment of CD8+ macrophages during Wallerian degeneration in the peripheral and central nervous system

The strong macrophage response occurring during Wallerian degeneration in the peripheral but not central nervous system has been implicated in tissue remodeling and growth factor production as key requirements for successful axonal regeneration. We have previously identified a population of CD8+ phagocytes in ischemic brain lesions that differed in its recruitment pattern from CD4+ macrophages/microglia found in other lesion paradigms. In the present study we show that crush injury to the sciatic nerve induced strong infiltration by CD8+ macrophages both at the crush site and into the degenerating distal nerve stump. At the crush site, CD8+ macrophages appeared within 24 hours whereas infiltration of the distal nerve parenchyma was delayed to the second week. CD8+ macrophages were ED1+ and CD11b+ but always MHC class II-. Most CD8+ macrophages coexpressed CD4 while a significant number of CD4+/CD8-macrophages was also present. Expression of the resident tissue macrophage marker ED2 was largely restricted to the CD4+/CD8- population. Following intraorbital crush injury to the optic nerve, infiltration of CD8+ macrophages was strictly confined to the crush site. Taken together, our study demonstrates considerable spatiotemporal diversity of CD8+ macrophage responses to axotomy in the peripheral and central nervous system that may have implications for the different extent of axonal regeneration observed in both systems.     

Traffic of leukocytes in the central nervous system is associated with chemokine up-regulation in a severe model of herpes simplex encephalitis: An intravital microscopy study

Herpes simplex virus type 1 (HSV-1) is a human pathogen that may cause severe encephalitis. The development of experimental models of HSV-1 encephalitis is relevant for the comprehension of the immune mechanisms involved in this infection. C57BL/6 mice were inoculated intracranially with 10⁴ PFU of neurotropic HSV-1. All animals developed signs of encephalitis and died until day 6 post-infection (pi). Using intravital microscopy, we demonstrated increased leukocyte rolling and adhesion in the brain microvasculature of infected mice at days 1, 3 and 5 pi. The infection was followed by a significant increase in chemokine levels, including CCL2, CCL3, CCL5, CXCL1 and CXCL9. TNF-α also showed a significant increase at day 3 pi. Histological analyses demonstrated diffuse meningoencephalitis characterized mainly by mononuclear cell infiltrates. The present model of HSV-1 encephalitis exhibits high mortality in the very first days of infection. Accordingly, there were increased rolling and adhesion of leukocytes along the brain endothelium wall and a high expression of chemokines in the central nervous system. These results corroborate the role of chemokines in leukocyte recruitment following HSV-1 infection in the central nervous system.     

The CC chemokine receptor 5 delta32 mutation is not associated with inflammatory bowel disease (IBD) in NE England

Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases of the gastrointestinal tract of unknown aetiology. Evidence of abnormalities in immune regulation and cytokine production in patients with IBD has led to investigations of various immuno-regulatory genes as potential candidate susceptibility loci. Studies using whole genome scanning have highlighted chromosomes 3, 7, 12 and 16. A 32 base-pair deletion in the CC-chemokine receptor-5 gene (CCR5-A32, chromosome 3p21.3) has been associated with susceptibility to IBD. We have investigated CCR5 as a candidate susceptibility gene in 350 patients (251 with ulcerative colitis and 99 with Crohn's disease) and 103 controls using polymerase chain reaction. There were no significant differences in the distribution of CCR5 genotypes or frequencies comparing patients and controls, or associations with extent of colitis. In contrast to preliminary data, these findings suggest no evidence for involvement of this mutation in susceptibility/resistance or disease progression in IBD.     

CC chemokine receptor 5 and CXC chemokine receptor 6 expression by lung CD8+ cells correlates with chronic obstructive pulmonary disease severity

Chronic obstructive pulmonary disease (COPD) is a progressive disease associated with a cellular inflammatory response. CD8(+) T cells are implicated in COPD pathogenesis, and their numbers significantly correlate with the degree of airflow limitation. Dendritic cells (DCs) are important sentinel immune cells, but little is known about their role in initiating and maintaining the CD8 T-cell response in COPD. To investigate the mechanisms for CD8(+) T-cell recruitment to the lung, we used resected human lung tissue to analyze chemokine receptor expression by CD8(+) T cells and chemokine production by CD1a(+) DCs. Among 11 surveyed chemokine receptors, only CC chemokine receptor (CCR5), CXC chemokine receptor (CXCR) 3, and CXCR6 correlated with COPD severity as defined by criteria from the Global Initiative for Chronic Obstructive Lung Disease. The CD8(+) T cells displayed a Tc1, CD45RA(+) effector memory phenotype. CD1a(+) DCs produced the respective ligands for CCR5 and CXCR3, CCL3 and CXCL9, and levels correlated with disease severity. CD1a(+) DCs also constitutively expressed the CXCR6 ligand, CXCL16. In conclusion, we have identified major chemokine elements that potentially mediate CD8(+) T-cell infiltration during COPD progression and demonstrated that CD1a(+) mucosal-associated DCs may sustain CD8(+) T-cell recruitment/retention. Chemokine targeting may prove to be a viable treatment approach.     

Cation-dependent structures associated with membranes in the rat central nervous system.

As observed by high magnification electron microscopy, potassium ions induce osmiophilia at the extracellular side of triple layered plasma membranes in the central nervous system of the rat. In contrast, sodium ions induce a widening of the intracellular lamina of these membranes, and do not result in observable extracellular deposits. The observations suggest the existence of potassium and sodium ion-selective structures associated with opposite surfaces of the neuron membrane. Use of the fixative vehicle as a cytochemical reagent is proposed.     

Central nervous system fibrosis is associated with fibrocyte-like infiltrates

Fibrotic wall formation is essential for limiting pathogen dissemination during brain abscess development. However, little is known about the regulation of fibrotic processes in the central nervous system (CNS). Most CNS injury responses are associated with hypertrophy of resident astrocytes, a process termed reactive gliosis. Studies of fibrosis outside the CNS have identified two bone marrow-derived cell types, fibrocytes and alternatively activated M2 macrophages, as key mediators of fibrosis. The current study used bone marrow chimeras generated from green fluorescent protein transgenic mice to evaluate the appearance of these cell types and whether bone marrow-derived cells were capable of acquiring fibrotic characteristics during brain abscess development. Immunofluorescence staining revealed partial overlap between green fluorescent protein, α-smooth muscle actin, and procollagen, suggesting that a population of cells forming the brain abscess capsule originate from a bone marrow precursor. In addition, the influx of fibrocyte-like cells into brain abscesses immediately preceded the onset of fibrotic encapsulation. Fibrotic wall formation was also associated with increased numbers of alternatively activated M2 microglia and macrophages. To our knowledge, this is the first study demonstrating that bone marrow-derived infiltrates are capable of expressing fibrotic molecules during CNS inflammation.     

TLR4与中枢神经系统损伤

As a receptor mediating the transmembrane signal transduction in the innate immunity, Toll-like receptor 4 (TLR4) is a bridge between innate immunity and required immunity, and plays an important role when signal-transducing of some cells are activated. Recent reports show that TLR4 expresses in the different glial cells and strongly links to the innate immune activation and inflammatory response in the central nervous system (CNS). TLR4 plays a key role in the processes of brain damage by infection of the CNS, stroke, cerebral hemorrhage and trauma. In this review, we concentrate on recent findings regarding the progress of function and mechanism of TLR4 in the processes of the CNS damage in various diseases.