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The Local and Peripheral Immune Responses to Stroke: Implications for Therapeutic Development.

ABSTRACT: The immune response to stroke is an exciting target for future stroke therapies. Stroke is a leading cause of morbidity and mortality worldwide, and clot removal (mechanical or pharmacological) to achieve tissue reperfusion is the only therapy currently approved for patient use. Due to a short therapeutic window and incomplete effectiveness, however, many patients are left with infarcted tissue that stimulates inflammation. Although this is critical to promote repair, it can also damage surrounding healthy brain tissue. In addition, acute immunodepression and subsequent infections are common and are associated with worse patient outcomes. Thus, the acute immune response is a major focus of researchers attempting to identify ways to amplify its benefits and suppress its negative effects to improve short-term recovery of patients. Here we review what is known about this powerful process. This includes the role of brain resident cells such as microglia, peripherally activated cells such as macrophages and neutrophils, and activated endothelium. The role of systemic immune activation and subsequent immunodepression in the days after stroke is also discussed, as is the chronic immune responses and its effects on cognitive function. The biphasic role of inflammation, as well as complex timelines of cell production, differentiation, and trafficking, suggests that the relationship between the acute and chronic phases of stroke recovery is complex. Gaining a more complete understanding of this intricate process by which inflammation is initiated, propagated, and terminated may potentially lead to therapeutics that can treat a larger population of stroke patients than what is currently available. The immune response plays a critical role in patient recovery in both the acute and chronic phases after stroke. In patients, the immune response can be beneficial by promoting repair and recovery, and also detrimental by propagating a pro-inflammatory microenvironment. Thus, it is critical to understand the mechanisms of immune activation following stroke in order to successfully design therapeutics.

SUBMITTER: Zera KA

PROVIDER: S-EPMC7283378 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The skin has developed a hierarchy of systems that encompasses the skin immune and local steroidogenic activities in order to protect the body against the external environment and biological factors and to maintain local homeostasis. Most recently it has been established that skin cells contain the entire biochemical apparatus necessary for production of glucocorticoids, androgens and estrogens either from precursors of systemic origin or, alternatively, through the conversion of cholesterol to pregnenolone and its subsequent transformation to biologically active steroids. Examples of these products are corticosterone, cortisol, testosterone, dihydrotesterone and estradiol. Their local production can be regulated by locally produced corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) or cytokines. Furthermore the production of glucocorticoids is affected by ultraviolet B radiation. The level of production and nature of the final steroid products are dependent on the cell type or cutaneous compartment, e.g., epidermis, dermis, adnexal structures or adipose tissue. Locally produced glucocorticoids, androgens and estrogens affect functions of the epidermis and adnexal structures as well as local immune activity. Malfunction of these steroidogenic activities can lead to inflammatory disorders or autoimmune diseases. The cutaneous steroidogenic system can also have systemic effects, which are emphasized by significant skin contribution to circulating androgens and/or estrogens. Furthermore, local activity of CYP11A1 can produce novel 7?-steroids and secosteroids that are biologically active. Therefore, modulation of local steroidogenic activity may serve as a new therapeutic approach for treatment of inflammatory disorders, autoimmune processes or other skin disorders. In conclusion, the skin can be defined as an independent steroidogenic organ, whose activity can affect its functions and the development of local or systemic inflammatory or autoimmune diseases. This article is part of a Special Issue entitled 'CSR 2013'.

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The Local and Peripheral Immune Responses to Stroke: Implications for Therapeutic Development.

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