Nuanced roles of cytokines in three major human brain disorders

Abstract

The three most prevalent human disorders of the CNS in which immunity and inflammation are likely to have vital roles (excluding infection of the CNS) are fever, multiple sclerosis (MS), and Alzheimer disease (AD). As reviewed here, cytokines are critical in the induction of fever, the pathogenesis of MS, and the pathobiology of AD. Indeed, antibodies targeting cytokines have been used as a therapy for individuals with unusual and persistent febrile reactions not responsive to common antipyretics, while a recombinant cytokine is the most popular treatment for the relapsing-remitting form of MS. Although cytokine-modulating therapies are not currently in clinical use for the treatment of AD, cytokines can ameliorate disease pathology in certain experimental models of AD, suggesting a potential for future therapeutic opportunities.

Figure 1. Comparison of the humoral and neuronal hypotheses for fever induction.

According to the humoral hypothesis of fever induction, the pyrogenic cytokines IL-1, IL-6, and TNF-α gain access to the hypothalamus via fenestrations in the BBB in the circumventricular organs or via active transport mechanisms mediated by the cells surrounding the hypothalamus. A key feature of the humoral hypothesis is that the pyrogenic cytokines activate the febrile response indirectly, by inducing local endothelial cells or microglial cells to secrete PGE₂. The PGE₂ then acts via prostaglandin E receptor 3 to initiate a neuronal response that regulates the body temperature. According to the neuronal hypothesis, C5a stimulates PGE₂ production in the liver, and signaling to the hypothalamus occurs via a neural pathway mediated by the vagus nerve and the nucleus tractus solitarius.

Figure 2. Many cytokines influence the pathogenesis of MS.

MS is a neurodegenerative autoimmune disease of the white matter of the CNS in which cytokines have an important role. Some cytokines, such as IL-6, IL-17, TGF-β, and IFN-γ, trigger an inflammatory response in the white matter of the brain. Such inflammatory responses contribute to the development of plaques (the characteristic pathology of MS) in the white matter by stripping myelin from neurons. Other molecules that regulate cytokines (e.g., osteopontin [OPN]) may increase Th17 and IFN-γ production. In addition, the most popular treatment for individuals with MS is the cytokine IFN-β, which is though to attenuate the action of the proinflammatory cytokines. Depicted are other potential therapies that may involve blockade of IFN-γ, IL-6, IL-12, or IL-23. Therapies aimed at blocking the adaptive immune response include DNA vaccination to induce tolerance. Statins and Copaxone are aimed at treatment of innate immune pathways and at the immune synapse. The most potent approved therapy for MS, natalizumab, blocks α₄β₁ integrin (verly late antigen 4 [VLA4]) interactions with VCAM. Depletion of B cells with anti-CD20 may be a promising therapeutic approach (all these approaches are discussed in refs. , , and 64). Adapted with permission from Nature Reviews. Immunology (23).