No quiet surrender: molecular guardians in multiple sclerosis brain

Abstract

The brain under immunological attack does not surrender quietly. Investigation of brain lesions in multiple sclerosis (MS) reveals a coordinated molecular response involving various proteins and small molecules ranging from heat shock proteins to small lipids, neurotransmitters, and even gases, which provide protection and foster repair. Reduction of inflammation serves as a necessary prerequisite for effective recovery and regeneration. Remarkably, many lesion-resident molecules activate pathways leading to both suppression of inflammation and promotion of repair mechanisms. These guardian molecules and their corresponding physiologic pathways could potentially be exploited to silence inflammation and repair the injured and degenerating brain and spinal cord in both relapsing-remitting and progressive forms of MS and may be beneficial in other neurologic and psychiatric conditions.

Figure 2. Mechanism of action of dimethylfumarate in the NRF2 pathway.

Inflammation and oxidative stress are thought to promote tissue damage and MS, and recent data point to a protective role for antioxidant pathways, including the transcription factor NRF2, in MS. The drug dimethylfumarate, which targets the NRF2 pathway, is approved for treatment of RRMS and is under investigation in clinical trials for progressive forms of MS. Dimethylfumarate has pleiotropic mechanisms of action, but activation of NRF2 accounts for some of its antiinflammatory activity. (A) KEAP1, which is part of a cullin family E3 ubiquitin ligase complex, normally mediates ubiquitination and proteasomal degradation of NRF2. (B) When KEAP1 undergoes sulfhydration of cysteine 151 via binding of fumarate, it becomes unable to interact with NRF2, which accumulates in the nucleus and induces the expression of NRF2-dependent antioxidant and cytoprotective genes. Activation of NRF2 leads to increased production of a spectrum of antioxidants, including glutathione and cystathionine.

Figure 1. Natalizumab blocks lymphocyte homing in MS.

(A) α4 integrin binds to vascular cell adhesion molecule 1 (VCAM1) on inflamed brain endothelium. This interaction gives lymphocytes access to the CNS. The presence of immune cells in the brain is a prominent feature of MS. (B) Natalizumab, a humanized antibody against α4 integrin, blocks binding of lymphocytes to VCAM on inflamed brain endothelium, thereby preventing lymphocyte entry into the CNS. Reproduced with permission from ref. (Used with permission: © 2012 Steinman. Journal of Cell Biology. 199:413–416. doi: 10.1083/jcb.201207175).