Abstract
Psychiatric disorders are highly prevalent and disabling conditions of increasing public health relevance. Much recent research has focused on the role of cytokines in the pathophysiology of psychiatric disorders; however, the related family of immune proteins designated chemokines has been relatively neglected. Chemokines were originally identified as having chemotactic function on immune cells; however, recent evidence has begun to elucidate novel, brain-specific functions of these proteins of relevance to the mechanisms of psychiatric disorders. A systematic review of both human and animal literature in the PubMed and Google Scholar databases was undertaken. After application of all inclusion and exclusion criteria, 157 references were remained for the review. Some early mechanistic evidence does associate select chemokines with the neurobiological processes, including neurogenesis, modulation of the neuroinflammatory response, regulation of the hypothalamus–pituitary–adrenal axis, and modulation of neurotransmitter systems. This early evidence however does not clearly demonstrate any specificity for a certain psychiatric disorder, but is primarily relevant to mechanisms which are shared across disorders. Notable exceptions include CCL11 that has recently been shown to impair hippocampal function in aging – of distinct relevance to Alzheimer’s disease and depression in the elderly, and pre-natal exposure to CXCL8 that may disrupt early neurodevelopmental periods predisposing to schizophrenia. Pro-inflammatory chemokines, such as CCL2, CCL7, CCL8, CCL12, and CCL13, have been shown to drive chemotaxis of pro-inflammatory cells to the inflamed or injured CNS. Likewise, CX3CL has been implicated in promoting glial cells activation, pro-inflammatory cytokines secretion, expression of ICAM-1, and recruitment of CD4+ T-cells into the CNS during neuroinflammatory processes. With further translational research, chemokines may present novel diagnostic and/or therapeutic targets in psychiatric disorders.
Highlights
Psychiatric disorders are highly prevalent and disabling conditions of increasing public health relevance (Whiteford et al, 2013)
One area of neuroscience which has yet to receive such a translational approach is the increasing recognition of central nervous system (CNS)-specific mechanisms of the immune proteins designated as chemokines
This review aims to systematically evaluate the immune and non-immune mechanisms by which chemokines may contribute to the pathophysiology or pathogenesis of psychiatric disorders both in adulthood and early neurodevelopmental periods
Summary
Psychiatric disorders are highly prevalent and disabling conditions of increasing public health relevance (Whiteford et al, 2013). Chemokines act through common intracellular signaling mechanisms to increase intracellular calcium (Nelson and Gruol, 2004) and their direct signaling is through G-protein-coupled receptors (Baggiolini et al, 1997) These chemotactic proteins are known to be important for leukocyte migration and activation under both physiological and pathological conditions. Chemokines have long been recognized to have additional functions, including inducing the release of pro-inflammatory mediators and control of T-helper (Th)-1/Th-2 phenotypic polarization (Cyster, 1999). They have been categorized functionally into homeostatic and inflammatory chemokines The former being always expressed in constitutive levels in certain organs and tissues and are required for basal immune cells migration, for example migration of the dendritic cells to the local-draining lymph nodes, where they activate more antigen-specific T cells. The latter, on the other hand, are expressed under the influence of pro-inflammatory factor, for example LPS, TNF-α, IL-1β) and further participate to upregulate the inflammatory response by attracting immune cells (e.g., macrophages, fibroblasts, T cells) to the site of inflammation (Rossi and Zlotnik, 2000; Zlotnik and Yoshie, 2000)
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