Paradoxical Effect of Cortistatin Treatment and Its Deficiency on Experimental Autoimmune Encephalomyelitis

Abstract

Cortistatin is a cyclic-neuropeptide produced by brain cortex and immune cells that shows potent anti-inflammatory activity. In this article, we investigated the effect of cortistatin in two models of experimental autoimmune encephalomyelitis (EAE) that mirror chronic and relapsing-remitting multiple sclerosis. A short-term systemic treatment with cortistatin reduced clinical severity and incidence of EAE, the appearance of inflammatory infiltrates in spinal cord, and the subsequent demyelination and axonal damage. This effect was associated with a reduction of the two deleterious components of the disease, namely, the autoimmune and inflammatory response. Cortistatin decreased the presence/activation of encephalitogenic Th1 and Th17 cells in periphery and nervous system, and downregulated various inflammatory mediators, whereas it increased the number of regulatory T cells with suppressive effects on the encephalitogenic response. Moreover, cortistatin regulated glial activity and favored an active program of neuroprotection/regeneration. We further used cortistatin-deficient mice to investigate the role of endogenous cortistatin in the control of immune responses. Surprisingly, cortistatin-deficient mice were partially resistant to EAE and other inflammatory disorders, despite showing competent inflammatory/autoreactive responses. This unexpected phenotype was associated with elevated circulating glucocorticoids and an anxiety-like behavior. Our findings provide a powerful rationale for the assessment of the efficacy of cortistatin as a novel multimodal therapeutic approach to treat multiple sclerosis and identify cortistatin as a key endogenous component of neuroimmune system.

Cortistatin reduces atherosclerosis in hyperlipidemic ApoE-deficient mice and the formation of foam cells

“…Cortistatin is a neuropeptide that has recently emerged as a potent anti-inflammatory factor with capacity to regulate self-reactive responses in various experimental models of autoimmune disorders14161718. In this study, we provide evidence that cortistatin could be considered a protective therapy for cardiovascular disorders that course with exacerbated inflammatory and autoimmune responses, such as atherosclerosis.…”

“…In agreement, cortistatin-deficient mice responded to neointimal lesion with exacerbated vascular responses11. Finally, cortistatin regulates both innate and adaptive immune responses in many inflammatory and autoimmune disorders, including experimental autoimmune myocarditis, collagen-induced arthritis, experimental autoimmune encephalomyelitis and inflammatory bowel disease814161718.…”

Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

“…CST also exerted beneficial long lasting effects in models of chronic and relapsing-remitting EAE, where systemic treatment with the neuropeptide reduced incidence and severity of the disease [169]. CST treatment reduced inflammatory spinal cord infiltrates, decreased activation of autoreactive Th1/Th17 cells, and inhibited expression of proinflammatory mediators, while promoting regulatory T cell differentiation.…”

“…CST treatment reduced inflammatory spinal cord infiltrates, decreased activation of autoreactive Th1/Th17 cells, and inhibited expression of proinflammatory mediators, while promoting regulatory T cell differentiation. The protective effects of CST were associated with its ability to promote the development of a glial neuroprotective phenotype, by inducing BDNF and activity-dependent neuroprotector protein release from neuron-glial cocultures, reducing astrocyte and microglial IL-6, TNF- α , and NO release, and preventing oxidative stress-induced oligodendrocyte death [169]. …”

Modulation of Immune Checkpoints and Graft-versus-Leukemia in Allogeneic Transplants by Antagonizing Vasoactive Intestinal Peptide Signaling

“…These data suggest distinct pathologic mechanisms for VIP in autoimmunity based upon differences in T-cell homing or tolerance. PACAP-treatment also protected against EAE(49), and the pharmacological activity of PACAP in VIP-KO mice was potentiated by up-regulation or hypersensitization of VIP-related receptors PAC and VPAC(50). Thus these data indicate a complex role for VIP in different models of autoimmune diseases.…”