Critical role for PDE4 subfamilies in the development of experimental autoimmune encephalomyelitis
Journal of Chemical Neuroanatomy. 2013-01-01; 47: 96-105
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Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple
sclerosis exhibiting neuroinflammation, axonal damage and demyelination, further
characterized by T- and B-cell responses to myelin oligodendrocyte glycoprotein.
Pharmacological manipulation of phosphodiesterases (PDEs) provokes profound
anti-inflammatory responses through modulation of cAMP levels. The PDE4B
subfamily has been related to the inflammatory immune response in mice and PDE4
inhibition produces amelioration of the clinical signs and delayed onset in the
EAE model. Analyses of the expression of the mRNA coding for PDE4B splice
variants revealed an upregulation of PDE4B2 in the brainstem and spinal cord of
EAE mice which correlated with forkhead box P3 (FoxP3) and transforming growth
factor beta (TGF-β) mRNAs expression in a score-dependent manner. The increase
observed for the PDE4B protein was mainly found in antigen-presenting cells
(APCs) such as dendritic cells and microglia/macrophages, in areas with high
cellular infiltration. Unexpectedly, PDE4B(-/-) mice showed an earlier onset of
the disease compared to wildtype mice. The results point to a possible role of
the PDE4B enzyme and in particular the PDE4B2 splice variant during EAE
pathogenesis, probably by modulating cAMP levels in APCs, consequently
influencing the cytokine environment important for T-cell differentiation.
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