Sex differences in the neuro-immune consequences of stress: Focus on depression and anxiety

Abstract

Women appear to be more vulnerable to the depressogenic effects of inflammation than men. Chronic stress, one of the most pertinent risk factors of depression and anxiety, is known to induce behavioral and affective-like deficits via neuroimmune alterations including activation of the brain's immune cells, pro-inflammatory cytokine expression, and subsequent changes in neurotransmission and synaptic plasticity within stress-related neural circuitry. Despite well-established sexual dimorphisms in the stress response, immunity, and prevalence of stress-linked psychiatric illnesses, much of current research investigating the neuroimmune impact of stress remains exclusively focused on male subjects. We summarize and evaluate here the available data regarding sex differences in the neuro-immune consequences of stress, and some of the physiological factors contributing to these differences. Furthermore, we discuss the extent to which sex differences in stress-related neuroinflammation can account for the overall female bias in stress-linked psychiatric disorders including major depressive disorder and anxiety disorders. The currently available evidence from rodent studies does not unequivocally support the peripheral inflammatory changes seen in women following stress. Replication of many recent findings in stress-related neuroinflammation in female subjects is necessary in order to build a framework in which we can assess the extent to which sex differences in stress-related inflammation contribute to the overall female bias in stress-related affective disorders.

Keywords: Female; Neuroinflammation; Sex differences; Stress.

Figure 1

Sex differences in stress-induced inflammation in humans and rodents. The number of the black and red boxes indicate the extent of data supporting each phenomenon based on human studies (referenced in sections 4.1.1 and 4.1.2) that directly compared men and women. The thickness of the blue and red lines corresponds to the extent of available data supporting each phenomenon based on studies (referenced in sections 4.1.1, 4.1.2, and 4.2.3) that included both sexes. The pink box represents the behavioral consequences of low-dose endotoxin administration in healthy humans. Thick line: documented by ≥ 2 studies, thin line: 1 study, dotted line: phenomenon was found not to occur in the indicated sex. LPS, lipopolysaccharide; GC, glucocorticoid. References: 1.1. Depressed mood: (Eisenberger et al 2009, Engler et al 2015, Lasselin et al 2016, Moieni et al 2015). Social disconnectedness: (Eisenberger et al 2009, Moieni et al 2015). Activation of social pain circuitry: (Eisenberger et al 2009). Interferon-induced depression: (Bonaccorso et al 2002, Koskinas et al 2002, Udina et al 2012b). 1.2. Leukocytosis: (Maes et al 1999, Pehlivanoglu et al 2012). Induction of cytokines by stress: (Endrighi et al 2016). Suppression of LPS-induced cytokines: (Prather et al 2009). Increased GC sensitivity: (Rohleder et al 2006, Rohleder et al 2001). 1.3. Chronic stress-driven decreases in cellular immunity: (Flynn et al 2009). 2.1. Microglial activation: (Caetano et al 2016, Diz-Chaves et al 2013, Diz-Chaves et al 2012). Increased cytokine expression: (Bronson & Bale 2014, Diz-Chaves et al 2013, Diz-Chaves et al 2012). Increased cytokine receptor expression: (Viviani et al 2014). Priming by previous stress exposure: (Hudson et al 2014, Pyter et al 2013). Leukocyte infiltration: (Ataka et al 2013, Brevet et al 2010).