**3.2.1 HPA axis & CRH: Response to systemic stress**

The HPA axis originates from the CRH neurons in the parvocellular subdivision of the PVN of hypothalamus, while the sympathetic nervous system is under the regulation of brainstem locus coeruleus (LC), clustered with noradrenaline neurons. Morphological and immunocytochemical studies have demonstrated that reciprocal projections exist between PVN–CRH neurons and LC–NE neurons, forming a CRH–NE–CRH loop, which plays an important role in the stressful responses (Maier, 2003) (Pacak et al., 1998) (Pacak et al., 1995). Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH) (Tsigos et al., 2002). The gene for CRH is expressed, not only in the brain, but also in extracranial tissues, (Orth, 1992) (Owens et al., 1991) including normal mammalian skin (Slominski et al., 1995) (**a**Slominski et al., 1993) (bSlominski et al., 1993) (Ermak et al., 1997) (Slominski et al., 1998). It has been proposed that an equivalent to the hypothalamicpituitary-adrenal axis functions in mammalian skin, in response to local stress (**a**Slominski et al., 1996).

#### **3.2.2 HPA axis & CRH: Response to local stress**

It has been known for several years that the CRH/ POMC skin system fulfils analogous (pro-opiomelanocortin) functions to the HPA stress axis. CRH is the central trigger of HPA axis, and together with related peptides urocortin I–III that are the most important elements of the body response to stress. These elements regulate behavioral, autonomic, endocrine, reproductive, cardiovascular, gastro-intestinal, metabolic and immune systemic functions (Aguilera et al., 2001) (Grammatopoulos et al., 2002). Other actions of CRH include local immunomodulatory (predominantly proinflammatory) effects (Karalis et al., 1991) (Slominski et al., 2003), differing from a central immunosuppressive activity (through the HPA axis) (Chrousos 1995). Moreover, expression of CRH and regulated activity of CRH receptor type 1 (CRH1) can also play an important role in regulation of local stress response in peripheral tissues including skin, gastrointestinal tract or reproductive system. In humans, expression of at least eight variants of CRH1 mRNA (α, β, c, d, e, f, g and h) was detected and alternative splicing was found to be regulated by diverse physiological and

Psoriasis and Stress – Psoriasis Aspect of Psychoneuroendocrinology 193

interactions of the HPA axis and the immune/inflammatory reaction by being reciprocally connected with the CRH system, by receiving and transmitting humoral and nervous immune signals from the periphery, by densely innervating both primary and secondary lymphoid organs, and by reaching all sites of inflammation via the postganglionic sympathetic neurons. When activated during stress, the autonomic system exerts its own direct effects on immune organs, which can be immunosuppressive, or both immunopotentiating and antiinflammatory. CRH secreted by postganglionic sympathetic neurons at inflammatory sites has proinflammatory properties (immune *CRH*); one of its

The epidermis and its array of appendages undergo ongoing renewal by a process called homeostasis. Stem cells in the epidermis have a crucial role in maintaining tissue homeostasis by providing new cells to replace those that are constantly lost during tissue turnover or following injury (Blanpain et al., 2009). A homeostatic process involved in the maintenance of an internal steady state within a defined tissue of an organism, including control of cellular proliferation and death(apoptosis) and control of metabolic function. Mammalian epidermis is a stratified epithelium that retains the ability to self renews under both homeostatic and injury conditions by maintaining a population of mitotically active cells in the hair follicles and innermost basal layer (Niemann et al., 2002) (Ito et al., 2005). The basic mechanisms and signalling pathways that orchestrate epithelial morphogenesis in the skin have been designed for protective effect of this organ. The stratum corneum is the outermost of the 5 layers of the epidermis and is largely responsible for the vital barrier function of the skin. The physical barrier localized primarily in the stratum corneum and consists of protein-enriched cells (corneocytes with cornified envelope and cytoskeletal elements, as well as corneodesmosomes) and lipidenriched intercellular domains. The nucleated epidermis, with its tight, gap and adherens junctions, additional desmosomes and cytoskeletal elements, also contributes to the barrier. Lipids are synthesized in the keratinocytes during epidermal differentiation and are then extruded into the extracellular domains, where they form lipid-enriched extracellular layers (Jensen et al., 2009). Activation of HPA axis with release of stress neuropeptides is essential for biological homeostasis and responses to external and

More than ten years ago a comprehensive model of the skin acting as neuroendocrine organ has been proposed (Milstone et al., 1988) (**a**Slominski et al., 2000). For example, the skin synthesizes vitamin D, which enters the circulation and, upon activation, exerts profound metabolic and endocrine effects (Kragballe et al., 1996). Although the concept is still evolving, it relies on the skin capacity to communicate with the central system and to regulate global homeostasis through local production and/or systemic release of classical hormones, neuropeptides, neurotransmitters and biological regulators (**b**Slominski et al.,

key actions is to degranulate mast cells (Elenkov, 1999).

internal challenges (Lotti et al., 1999) (**b**Slominski et al., 1996).

**4.2 Skin – Neuroendocrine organ** 

2000).

**4.1 Skin (epidermal barrier homeostasis)** 

**4. Overview of skin** 

pathological factors including: growth conditions, onset of labor during pregnancy or exposure to ultraviolet irradiation (Michal et al., 2010). Of note, locally produced CRH can directly regulate steroid hormone production by adrenals and gonads. Furthermore, CRH in the immune cells can induce production and release of POMC derived ACTH and betaendorphin peptides. In vertebrates these peptides interact with membrane-bound CRH-R1 and CRH-R2 (Grammatopoulos et al., 2002) (Hillhouse et al., 2002). Both receptor types belong to the group II subfamily of G protein-coupled receptors (GPCRs). In human skin, CRH-R1 is the major receptor, expressed in both epidermal, dermal and subcutis with CRH-R1α being the most prevalent isoform. The CRH-R2 gene was expressed solely in hair follicle keratinocytes and papilla fibroblasts, whereas CRH-R2 antigen was localized predominantly in hair follicles, sebaceous and eccrine glands, muscle and blood vessels (**a**Slominski et al., 2004). A hair follicle is a typical stress-responding mini organ with a peculiar immune system. The proximal epithelium of an anagen hair follicle is known to be an area of immune privilege within the hair follicle immune system, whose collapse may be crucial for the pathogenesis of alopecia areata (Christoph et al., 2000).

#### **3.3 HPA axis–immune system interactions**

It has been known for several decades that stress, whether inflammatory, traumatic or psychological, is associated with concurrent activation of the HPA axis. In the early 1990s, it also became apparent that cytokines and other humoral mediators of inflammation are potent activators of the central stress response, constituting the afferent limb of a feedback loop through which the immune/inflammatory system and the CNS communicate (Chrousos 1995). All three inflammatory cytokines, tumor necrosis factor-(TNF), interleukin-1β and interleukin-6 (IL-6) can cause stimulation of the HPA axis alone, or in synergy with each other (Chrousos, 1995) (Tsigos et al., 1997). There is evidence to suggest that IL-6, the main endocrine cytokine, plays the major role in the immune stimulation of the axis, especially in chronic inflammatory stress. Some of the activating effects of cytokines on the HPA axis may be exerted indirectly by stimulation of the central catecholaminergic pathways. Conversely, activation of the HPA axis has profound inhibitory effects on the inflammatory/immune response because virtually all the components of the immune response are inhibited by cortisol. Alterations of leukocyte traffic and function, decreases in production of cytokines and mediators of inflammation, and inhibition of the latter's effects on target tissues are among the main immunosuppressive effects of glucocorticoids (Chrousos, 1995) (Elenkov, 1999).

#### **3.4 HPA: The field of psychoneuroimmunology**

Studies on stress-associated immune dysregulation have interested scientists and clinicians in the field of psychoneuroimmunology (PNI). This field focuses on the interactions among the central nervous system (CNS), the endocrine system and the immune system, and the impact these interactions have on health. Modulation of the immune response by the CNS is mediated by a complex network of signals that function in bi-directional communication among the nervous, endocrine and immune systems. HPA and SAM axes are the two major pathways through which immune function can be altered. The efferent sympathetic/adrenomedullary system apparently participates in a major fashion in the interactions of the HPA axis and the immune/inflammatory reaction by being reciprocally connected with the CRH system, by receiving and transmitting humoral and nervous immune signals from the periphery, by densely innervating both primary and secondary lymphoid organs, and by reaching all sites of inflammation via the postganglionic sympathetic neurons. When activated during stress, the autonomic system exerts its own direct effects on immune organs, which can be immunosuppressive, or both immunopotentiating and antiinflammatory. CRH secreted by postganglionic sympathetic neurons at inflammatory sites has proinflammatory properties (immune *CRH*); one of its key actions is to degranulate mast cells (Elenkov, 1999).
