Role of Chemokines, Neuronal Projections, and the Blood-Brain Barrier in the Enhancement of Cerebral EAE Following Focal Brain Damage

Sun, Dong; Tani, Masanao; Newman, Tracey; Krivacic, Kimberly; Phillips, Marian J.; Chernosky, Ann; Gill, Pelvender; Wei, Tao; Griswold, Katherine J.; Ransohoff, Richard M.; Weller, Roy O.

doi:10.1093/jnen/59.12.1031

Cited by 37 publications

(15 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to the GFAP-IL6 mice, focal cortical cryolesion is associated with localized breakdown of the BBB and the induction of a proinflammatory state with increased expression of a number of chemokine genes including CCL5 and CCL12 (32). However, as we have shown (supplementary Fig.…”

Section: Discussionsupporting

confidence: 65%

Site-Specific Production of IL-6 in the Central Nervous System Retargets and Enhances the Inflammatory Response in Experimental Autoimmune Encephalomyelitis

Quintana¹,

Müller²,

Frausto³

et al. 2009

The Journal of Immunology

107

View full text Add to dashboard Cite

IL-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. To establish the role of site-specific production of IL-6 in autoimmunity, we examined myelin oligodendrocyte glycoprotein immunization-induced EAE in transgenic mice (GFAP-IL6) with IL-6 production restricted to the cerebellum. Myelin oligodendrocyte glycoprotein-immunized (Mi-) GFAP-IL6 mice developed severe ataxia but no physical signs of spinal cord involvement, which was in sharp contrast to Mi-wild type (WT) animals that developed classical EAE with ascending paralysis. Immune pathology and demyelination were nearly absent from the spinal cord, but significantly increased in the cerebellum of Mi-GFAP-IL6 mice. Tissue damage in the cerebellum in the Mi-GFAP-IL6 mice was accompanied by increased total numbers of infiltrating leukocytes and increased proportions of both neutrophils and B-cells. With the exception of IL-17 mRNA, which was elevated in both control immunized and Mi-GFAP-IL6 cerebellum, the level of other cytokine and chemokine mRNAs were comparable with Mi-WT cerebellum whereas significantly higher levels of IFN-γ and TNF-α mRNA were found in Mi-WT spinal cord. Thus, site-specific production of IL-6 in the cerebellum redirects trafficking away from the normally preferred antigenic site the spinal cord and acts as a leukocyte “sink” that markedly enhances the inflammatory cell accumulation and disease. The mechanisms underlying this process likely include the induction of specific chemokines, activation of microglia, and activation and loss of integrity of the blood-brain barrier present in the cerebellum of the GFAP-IL6 mice before the induction of EAE.

show abstract

Section: Discussionsupporting

confidence: 65%

Site-Specific Production of IL-6 in the Central Nervous System Retargets and Enhances the Inflammatory Response in Experimental Autoimmune Encephalomyelitis

Quintana¹,

Müller²,

Frausto³

et al. 2009

The Journal of Immunology

107

View full text Add to dashboard Cite

show abstract

“…This might be due to tissue-specific cues influencing the function of DC in the draining lymph nodes that allows them to imprint a CNS homing program that is different from EAE without a cryolesion. Enhancement and location of autoimmune inflammation in the brain following a focal cortical cryolesion injury initially involve chemokines, such as the macrophage chemoattractants CCL2 (MCP-1) and CCL12 (MCP-5), and the activities of afferent and efferent neuronal connections with the site of damage [129]. By analogy, similar factors may modulate or reactivate autoimmune inflammation in MS [129].…”

Section: Relationships Between Lymphatic Drainage Of the Brain And Nementioning

confidence: 99%

Vascular, glial, and lymphatic immune gateways of the central nervous system

et al. 2016

Self Cite

View full text Add to dashboard Cite

Immune privilege of the central nervous system (CNS) has been ascribed to the presence of a blood–brain barrier and the lack of lymphatic vessels within the CNS parenchyma. However, immune reactions occur within the CNS and it is clear that the CNS has a unique relationship with the immune system. Recent developments in high-resolution imaging techniques have prompted a reassessment of the relationships between the CNS and the immune system. This review will take these developments into account in describing our present understanding of the anatomical connections of the CNS fluid drainage pathways towards regional lymph nodes and our current concept of immune cell trafficking into the CNS during immunosurveillance and neuroinflammation. Cerebrospinal fluid (CSF) and interstitial fluid are the two major components that drain from the CNS to regional lymph nodes. CSF drains via lymphatic vessels and appears to carry antigen-presenting cells. Interstitial fluid from the CNS parenchyma, on the other hand, drains to lymph nodes via narrow and restricted basement membrane pathways within the walls of cerebral capillaries and arteries that do not allow traffic of antigen-presenting cells. Lymphocytes targeting the CNS enter by a two-step process entailing receptor-mediated crossing of vascular endothelium and enzyme-mediated penetration of the glia limitans that covers the CNS. The contribution of the pathways into and out of the CNS as initiators or contributors to neurological disorders, such as multiple sclerosis and Alzheimer’s disease, will be discussed. Furthermore, we propose a clear nomenclature allowing improved precision when describing the CNS-specific communication pathways with the immune system.

show abstract

“…Immunoneutralization of CCL12 reduced bronchial reactivity in this model [107]. CCL12 has also been implicated in the pathogenesis of experimental allergic encephalomyelitis [108]. Lipopolysaccharide injection results in increased CCL12 concentrations in murine liver, and these increases are abrogated in Kupffer celldepleted mice, suggesting that tissue macrophages are the source of CCL12 in vivo [109].…”

Section: Ccl12 (Mcp5)mentioning

confidence: 99%

Chemokines in the pathogenesis of liver disease: so many players with poorly defined roles

Simpson¹,

Henderson²,

Bone-Larson³

et al. 2003

Clinical Science

View full text Add to dashboard Cite

Many new chemokines have been described in recent years, resulting in a new classification of these chemoattractant proteins. The characterization of the biological functions of most chemokines relates to their ability to induce chemotaxis in circulating inflammatory cells. However, it is now clear that chemokines have a much wider biological role, including angiogenesis, carcinogenesis and involvement in the pathogenesis of HIV infection. Our understanding of the role of chemokines in the pathogenesis of disorders of the lungs and brain outstrips that with regard to disorders of the liver. An increased understanding of the role of chemokines in the pathogenesis of liver disease may lead to the development of novel therapies for hepatic disease.

show abstract

Role of Chemokines, Neuronal Projections, and the Blood-Brain Barrier in the Enhancement of Cerebral EAE Following Focal Brain Damage

Cited by 37 publications

References 42 publications

Site-Specific Production of IL-6 in the Central Nervous System Retargets and Enhances the Inflammatory Response in Experimental Autoimmune Encephalomyelitis

Site-Specific Production of IL-6 in the Central Nervous System Retargets and Enhances the Inflammatory Response in Experimental Autoimmune Encephalomyelitis

Vascular, glial, and lymphatic immune gateways of the central nervous system

Chemokines in the pathogenesis of liver disease: so many players with poorly defined roles

Contact Info

Product

Resources

About