Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease

Abstract

The last decade has witnessed profound growth in studies examining the role of fundamental neuroimmune processes as key mechanisms that might form a natural bridge between normal physiology and pathological outcomes. Rooted in core concepts from psychoneuroimmunology, this review utilizes a succinct, exemplar-driven approach of several model systems that contribute significantly to our knowledge of the mechanisms by which neuroimmune processes interact with stress physiology. Specifically, we review recent evidence showing that (i) stress challenges produce time-dependent and stressor-specific patterns of cytokine/chemokine expression in the CNS; (ii) inflammation-related genes exhibit unique expression profiles in males and females depending upon individual, cooperative or antagonistic interactions between steroid hormone receptors (estrogen and glucocorticoid receptors); (iii) adverse social experiences incurred through repeated social defeat engage a dynamic process of immune cell migration from the bone marrow to brain and prime neuroimmune function and (iv) early developmental exposure to an inflammatory stimulus (carageenin injection into the hindpaw) has a lasting influence on stress reactivity across the lifespan. As such, the present review provides a theoretical framework for understanding the role that neuroimmune mechanisms might play in stress plasticity and pathological outcomes, while at the same time pointing toward features of the individual (sex, developmental experience, stress history) that might ultimately be used for the development of personalized strategies for therapeutic intervention in stress-related pathologies.

Keywords: Corticosterone; cytokine; development; inflammation; neuroimmune; sex differences; steroid receptors; stress.

Figure 1. Glucocorticoid and Estradiol regulated genes in human uterine epithelial cells

Venn diagram of significantly regulated genes by Dexamethasone (Dex), Estradiol (E2) and the combination of Dex+E2 from microarray analysis performed in human uterine epithelial cells. Figure adapted from Whirledge et al., (PMID 23843231) with permission.

Figure 2. Microglia and CD11b+/CD45 Myeloid Cells Contribute to Social Defeat-Induced Prolonged Anxiety

The response to social defeat activates fear/threat appraisal circuitry in the brain. Activation of microglia in these areas results in the release proinflammatory cytokines including IL-1β and CCL2. In turn, these cytokine responses contribute to the development of a reactive endothelium in the regional neurovasculature. Social defeat also activates the HPA axis and SNS which stimulate the production of primed CD11+/CD45+ myeloid cells (MCs) in the bone marrow. Release of MCs into circulation results in trafficking of these cells to the reactive neurovasculature which is followed by adhesion and diapedesis into the brain. The activation of microglia and the trafficking of primed MCs results in the development of prolonged anxiety-behavior (Godbout & Sheridan, 2015).

Figure 3

Summary of key factors to be considered in the development of individualized treatment strategies for stress-related disorders.