Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates

Abstract

Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cell-nerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1

Central nervous system (CNS) response to psychological stress. Centrally, the hypothalamic-pituitary-adrenal axis (HPA) responds to psychological stress by upregulating the stress hormones corticotrophin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) (20, 21). Pituitary prolactin (PRL) increases and it abrogates stress-induced inhibition of lymphocyte proliferation (155). CRH and ACTH stimulate norepinephrine (NE) and cortisol release from the adrenal glands, and directly stimulate immune cells in the blood and periphery via their respective receptors. This outcome is regulated by negative feedback of cortisol (dashed arrow) on further CRH and ACTH release by the hypothalamus and pituitary hypophysis. Brainstem serotonin (5HT) production increases (20, 22, 156). Substance P (SP), gastrin-releasing peptide (GRP), and calcitonin gene related peptide (CGRP) in the dorsal root ganglia also increase (10). In the skin, immune cells release cytokines, chemokines, and neuropeptides that modulate local inflammatory responses. Sensory nerves release neuromediators that modulate cutaneous inflammation, pain, and pruritus, and transmit sensory stimuli via dorsal root ganglia and the spinal cord to specific areas of the CNS (10). Cutaneous mast cells are in close association with substance P (SP), CGRP, pituitary adenylate cyclase-activating protein (PACAP), and opioid-releasing neurons, and are receptive to these respective neuromediators (157). They synthesize and secrete many inflammatory mediators in response to various physical and biochemical stimuli (158). Local production of neurohormones and neuropeptides, with sprouting of SP+ nerve fibers, occurs in the skin in response to stress (9).