cortistatin-14 and Autoimmune-Diseases

Cortistatin is a neuropeptide isolated from cortical brain regions, showing high structural homology and sharing many functions with somatostatin. However, cortistatin exerts unique functions in the central nervous and immune systems, including decreasing locomotor activity, inducing sleep-promoting effects, and deactivating inflammatory and T helper (TH )1/TH 17-driven responses in preclinical models of sepsis, arthritis, multiple sclerosis, and colitis. Besides its release by cortical and hippocampal interneurons, cortistatin is produced by macrophages, lymphocytes, and peripheral nociceptive neurons in response to inflammatory stimuli, supporting a physiological role of cortistatin in the immune and nociceptive systems. Cortistatin-deficient mice have been shown to have exacerbated nociceptive responses to neuropathic and inflammatory pain sensitization. However, a paradoxical effect has been observed in studies of immune disorders, in which, despite showing competent inflammatory/autoreactive responses, cortistatin-deficient mice were partially resistant to systemic autoimmunity and inflammation. This unexpected phenotype was associated with elevated circulating glucocorticoids and anxiety-like behavior. These findings support cortistatin as a novel multimodal therapeutic approach to treat autoimmunity and clinical pain and identify it as a key endogenous component of the neuroimmune system related to stress responses.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Cerebral Cortex; Disease Models, Animal; Humans; Inflammation; Macrophages; Mice; Motor Activity; Neuropeptides; Nociceptors; Sleep; Somatostatin; Th1 Cells; Th17 Cells

Identification of the factors that regulate the immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of autoimmune diseases. Some neuropeptides and hormones have emerged as endogenous agents that participate in the regulation of the processes that ensure self-tolerance. Among them, cortistatin, an endogenous cyclic neuropeptide relative of somatostatin, has recently shown therapeutic potential for a variety of immune disorders. Here we examine the latest research findings, which indicate that cortistatin participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T cell effectors.

Topics: Amino Acid Sequence; Animals; Autoimmune Diseases; Immune Tolerance; Immunologic Factors; Molecular Sequence Data; Neuroimmunomodulation; Neuropeptides; Receptors, Neuropeptide; Somatostatin; T-Lymphocytes, Regulatory

The induction of immune tolerance is critical for the prevention of autoimmunity and the maintenance of immune homeostasis. The identification of factors involved in the maintenance or restoration of such tolerance has become the focus of new therapies for inflammatory and autoimmune diseases. Cortistatin, a recently discovered cyclic neuropeptide related to somatostatin, has emerged as a potential endogenous antiinflammatory factor based on its production by, as well as its binding to, immune cells. Thus, cortistatin has been found to downregulate the inflammatory response mediated by activated macrophages. The present work reviews various recent studies involving different experimental models of sepsis, rheumatoid arthritis and inflammatory bowel disease, demonstrating that cortistatin treatment offers great benefits at both the clinical and pathological levels. These include the downregulation of both inflammatory and Th1-mediated autoimmune disease components and the emergence of regulatory T cells (Treg) that suppress autoreactive T cells, both of which contribute to the restoration of immune tolerance. While many questions need to be resolved, cortistatin appears to be an exciting and promising candidate for the treatment of several chronic inflammatory diseases and autoimmune disorders.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Autoimmune Diseases; Clinical Trials as Topic; Humans; Immunologic Factors; Inflammation; Inflammatory Bowel Diseases; Macrophages; Neuropeptides; Shock, Septic; Th1 Cells

Somatostatin and cortistatin, a recently discovered endogenous neuropeptide relative of somatostatin, have multiple modulatory effects on the immune system. The specific somatostatin receptor distribution might in part explain the heterogeneity of effects of somatostatin or its analogs on immunocytes. In fact, somatostatin receptor subtypes are differentially expressed on specific cell subsets within the organs of the immune system and the expression is dynamically regulated and seems to depend on the traffic of these cells through and within lymphoid structure and homing in tissues. Somatostatin effects on immune cells are mainly based on autocrine and paracrine modes of action. In fact, activated cells producing somatostatin (or cortistatin) may interact with other cells expressing the receptors. Here, we review the postulated modes of action of somatostatin and somatostatin-like peptides, including the currently available synthetic somatostatin analogs, in cells of the immune system. We also discuss the wide distribution of somatostatin and its specific five receptor subtypes in immune cell lines, as well as throughout animal and human lymphoid organs, in both normal and pathological conditions.

Topics: Animals; Autoimmune Diseases; Granulomatous Disease, Chronic; Humans; Immune System; Neoplasms; Neuropeptides; Rats; Receptors, Somatostatin; Somatostatin; Tissue Distribution

Myocarditis is an inflammatory and autoimmune cardiovascular disease that causes dilated myocardiopathy and is responsible for high morbidity and mortality worldwide. Cortistatin is a neuropeptide produced by neurons and cells of the immune and vascular systems. Besides its action in locomotor activity and sleep, cortistatin inhibits inflammation in different experimental models of autoimmune diseases. However, its role in inflammatory cardiovascular disorders is unexplored. Here, we investigated the therapeutic effects of cortistatin in a well-established preclinical model of experimental autoimmune myocarditis (EAM).. We induced EAM by immunization with a fragment of cardiac myosin in susceptible Balb/c mice. Cortistatin was administered i.p. starting 7, 11 or 15 days after EAM induction. At day 21, we evaluated heart hypertrophy, myocardial injury, cardiac inflammatory infiltration and levels of serum and cardiac inflammatory cytokines, cortistatin and autoantibodies. We determined proliferation and cytokine production by heart draining lymph node cells in response to cardiac myosin restimulation.. Systemic injection of cortistatin during the effector phase of the disease significantly reduced its prevalence and signs of heart hypertrophy and injury (decreased the levels of brain natriuretic peptide) and impaired myocardial inflammatory cell infiltration. This effect was accompanied by a reduction in self-antigen-specific T-cell responses in lymph nodes and in the levels of cardiomyogenic antibodies and inflammatory cytokines in serum and myocardium. Finally, we found a positive correlation between cardiac and systemic cortistatin levels and EAM severity.. Cortistatin emerges as a new candidate to treat inflammatory dilated cardiomyopathy.

Topics: Animals; Autoimmune Diseases; Cardiomyopathy, Dilated; Cytokines; Disease Models, Animal; Female; Inflammation; Lymph Nodes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myocarditis; Neuropeptides; Severity of Illness Index; T-Lymphocytes; Time Factors