The emerging role of p38 mitogen-activated protein kinase in multiple sclerosis and its models

Abstract

Multiple sclerosis (MS), the most common disabling neurologic disease of young adults, is considered a classical T cell-mediated disease and is characterized by demyelination, axonal damage, and progressive neurological dysfunction. The currently available disease-modifying therapies are limited in their efficacy, and improved understanding of new pathways contributing to disease pathogenesis could reveal additional novel therapeutic targets. The p38 mitogen-activated protein kinase (MAPK) signaling pathway is known to be triggered by stress stimuli and to contribute to inflammatory responses. Importantly, a number of recent studies have identified this signaling pathway as a central player in MS and its principal animal model, experimental allergic encephalomyelitis. Here, we review the evidence from mouse and human studies supporting the role of p38 MAPK in regulating key immunopathogenic mechanisms underlying autoimmune inflammatory disease of the central nervous system and the potential of targeting this pathway as a disease-modifying therapy in MS.

Fig 1

Pathophysiology of multiple sclerosis: potential factors that cause MS and sequential events in disease progression. BBB, blood-brain barrier.

Fig 2

Overview of the p38 MAPK pathway. The four different members of the p38 MAPK group (p38α, p38β, p38γ, and p38δ) are activated by phosphorylation by MAPK kinases MKK3 and MKK6. These MKKs are phosphorylated by a large group of MKK kinases (MKKKs) that are activated in response to different stimuli, such as inflammatory mediators and environmental stress. p38 MAPKs mediated various cellular processes.

Fig 3

Mechanisms by which p38 MAPK influences EAE development and/or progression. Activation of p38 MAPK by cytokine receptors, histamine H1 receptor (H1R), T cell receptor (TCR) through the classical or alternative pathways, or osmotic (salt) stress promotes IL-17 production by CD4 Th17 cells. IL-17 contributes indirectly to CNS damage. Activation of p38 MAPK in response to Toll-like receptor (TLR) signals in antigen-presenting cells (macrophages and dendritic cells) or astrocytes/microglia can promote the production of inflammatory cytokines that can trigger CNS damage directly or indirectly. CNS damage is mediated primarily by loss of oligodendrocytes and myelin sheath covering neuronal axons.