Administration of a monomeric CCL2 variant to EAE mice inhibits inflammatory cell recruitment and protects from demyelination and axonal loss

Brini, Elena; Ruffini, Francesca; Bergami, A.; Brambilla, Elena; Dati, Gabriele; Greco, Béatrice; Cirillo, R; Proudfoot, Amanda E. I.; Comı, Gıancarlo; Furlan, Roberto; Zaratin, Paola; Martino, Gianvito

doi:10.1016/j.jneuroim.2009.01.022

Cited by 23 publications

(21 citation statements)

References 41 publications

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“…CCL2 mRNA expression in CNS lesions was seen to be up-regulated in murine EAE and neutralized with anti-CCL2 antibody, while DNA vaccination before immunization protected mice against EAE [31,32]. Furthermore, administration of a mutated CCL2 protein, which could perturb with chemotactic properties, inhibited cell recruitment and protected against demyelination and axonal loss in CNS lesions of EAE mice [33]. Our findings clearly showed that CCL2 was involved in both disease onset and recurrence.…”

Section: Discussionmentioning

confidence: 59%

Cytokine production profiles in chronic relapsing–remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are important participants in the first attack but not in the relapse

Hidaka

Inaba

Matsuda

et al. 2014

Journal of the Neurological Sciences

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Multiple sclerosis (MS) is a chronic demyelinating disease often displaying a relapsing-remitting course of neurological manifestations that is mimicked by experimental autoimmune encephalomyelitis (EAE) in animal models of MS. In particular, NOD mice immunized with myelin oligodendrocyte glycoprotein peptide 35-55 develop chronic relapsing-remitting EAE (CREAE). To elucidate the mechanisms that cause MS relapse, we investigated the histopathology and cytokine production of spleen cells and mRNA expression levels in the central nervous system (CNS) of CREAE mice. During the first attack, inflammatory cell infiltration around small vessels and in the subarachnoid space was observed in the spinal cord. Spleen cell production and mRNA expression in the CNS of several cytokines, including IFN-γ, TNF-α, IL-6, IL-17, and CC chemokine ligand 2 (CCL2), were higher in CREAE mice than in controls. Afterwards, parenchymal infiltration and demyelination were observed histologically in the spinal cord and corresponded with the more severe clinical symptoms of the first and second relapses. IL-17 and CCL2, but not IFN-γ, TNF-α, or IL-6, were also produced by spleen cells during recurrences. Our results suggested that the immune mechanisms in relapses were different from those in the first attack for CREAE. Further investigation of CREAE mechanisms may provide important insights into successful therapies for human relapsing-remitting MS.

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Section: Discussionmentioning

confidence: 59%

Cytokine production profiles in chronic relapsing–remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are important participants in the first attack but not in the relapse

Hidaka

Inaba

Matsuda

et al. 2014

Journal of the Neurological Sciences

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“…We also demonstrate that NLRX1 inhibits the production of CCL2. CCL2 recruits immune cells into damaged tissues (26) and promotes T cell migration to the CNS during EAE (27). Our findings show that enhanced expression of CCL2 in Nlrx1 Ϫ/Ϫ mice correlates with heightened T cell infiltration into the CNS.…”

Section: Discussionmentioning

confidence: 60%

The Nucleotide-binding Leucine-rich Repeat (NLR) Family Member NLRX1 Mediates Protection against Experimental Autoimmune Encephalomyelitis and Represses Macrophage/Microglia-induced Inflammation

Eitas

Chou

Wen

et al. 2014

Journal of Biological Chemistry

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“…Similarly, Luster and coworkers demonstrated that a monomeric form of CXCL10 (IP-10) is incapable of inducing cell migration in vivo and transendothelial migration in vitro (19). More recently it was shown that the above monomeric form of CCL2 has anti-inflammatory activity in animal models of experimental arthritis (20) and experimental autoimmune encephalomyelitis (EAE) (55), underscoring the importance of oligomerization in vivo.…”

Section: Discussionmentioning

confidence: 98%

NMR Analysis of the Structure, Dynamics, and Unique Oligomerization Properties of the Chemokine CCL27

Jansma

Kirkpatrick

Hsu

et al. 2010

Journal of Biological Chemistry

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Chemokines have two essential interactions in vivo, with G protein-coupled receptors, which activate intracellular signaling pathways, and with glycosaminoglycans (GAGs), which are involved in cell surface localization and transport. Although it has been shown that chemokines bind and activate their respective G protein-coupled receptors as monomers, many chemokines oligomerize upon GAG binding, and the ability to oligomerize and bind GAGs is required for in vivo function. In this study, we investigated the structure, dynamics, and oligomerization behavior of cutaneous T-cell-attracting chemokine (CTACK, also known as CCL27) by NMR.15 N relaxation and translational self-diffusion rates indicate that CCL27 oligomerizes, but in contrast to many other chemokines that form relatively discrete oligomers, CCL27 transitions between monomer, dimer, and tetramer species over a relatively narrow concentration range. A three-dimensional structure determination was pursued under conditions where CCL27 is primarily dimeric, revealing the standard motif for a chemokine monomer. Analysis of chemical shift perturbations of 1 H-15 N HSQC spectra, relaxation-dispersion experiments, and filtered nuclear Overhauser effects suggest that CCL27 does not adopt a discrete CXC or CC dimer motif. Instead, CCL27 has uncommon oligomerization behavior, where several equilibria involving relatively low affinity interactions between different interfaces seem to be simultaneously at work. However, interaction with heparin avidly promotes oligomerization under conditions where CCL27 is monomeric by itself. We hypothesize that the plasticity in the oligomerization state may enable CCL27 to adopt different oligomeric structures, depending on the nature of the GAG binding partner, thereby providing a mechanism for increased diversity and specificity in GAG-binding and GAGrelated functions.

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Administration of a monomeric CCL2 variant to EAE mice inhibits inflammatory cell recruitment and protects from demyelination and axonal loss

Cited by 23 publications

References 41 publications

Cytokine production profiles in chronic relapsing–remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are important participants in the first attack but not in the relapse

Cytokine production profiles in chronic relapsing–remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are important participants in the first attack but not in the relapse

The Nucleotide-binding Leucine-rich Repeat (NLR) Family Member NLRX1 Mediates Protection against Experimental Autoimmune Encephalomyelitis and Represses Macrophage/Microglia-induced Inflammation

NMR Analysis of the Structure, Dynamics, and Unique Oligomerization Properties of the Chemokine CCL27

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