**1. Introduction**

Psoriasis is a chronic inflammatory skin disease that mainly characterized by acanthosis, abnormal differentiation and infiltration of leukocytes from the dermis. The factors that causing this disease are genetic, environmental and inflammatory mediators [1]. In normal skin, the transformation of basal keratinocytes (KCs) to anucleate corneocytes process will takes within 50 days. Whereas, in psoriatic skin the epidermal cell cycle is rapid and the transformation occurs within 5 days. Thereby, the stratum corneum contains fully unmatured keratinized cells which build up abnormally and forms scales like structure. Due to this, epidermis of psoriatic lesions will become thicker and also blood vessels in the papillary layer of the dermis get dilated along with effusion of inflammatory cells, such as neutrophils, infiltrate the epidermis [2]. About 80% of the epidermal skin constitutes KCs. KC play a major role

in this chronic inflammatory disease. It play a special role in sensing epidermal barrier and regulating immune homeostasis [1].

### **1.1 Hyperproliferation of epidermis in psoriasis**

Until the late 1970s, the hypothesis of psoriasis arising from abnormalities in KCs was favored, and the abnormal proliferation was treated with antiproliferative agents. Since then, the participation of KC in the pathogenesis of psoriasis has certainly been overlooked. A publication by Zenz et al. [3] has highlighted again the role of KC in the pathomechanisms leading to psoriatic lesions. Their findings favor the view that psoriasis could also be regarded as a primary KC disorder amplified by the immune system [4]. While the debate will continue among skin biologists on the different theories, it is unquestionable that KC are potential initiators of inflammation, producing a number of cytokines, adhesion molecules and growth factors.

The growth of KC is regulated by a delicate balance between molecules that control cell survival and cell death. Thus, the thickness of human epidermis remains relatively constant throughout life. This regulation is disturbed in psoriasis that leads to KC hyperproliferation with the net result of an increase in the volume of cell mass [5]. The epidermal cell cycle of hyperproliferating psoriatic KC occurs within 5 days. Effusion of growth factors and inflammatory mediators from different skin cells, are believed to regulate the epidermal hyperproliferation in psoriasis (**Figure 1**) [6].

When skin cells exposed to any external factors such as environmental, chemical and internal factor like genetic, psychological and physical stress will probably activate immune cells within the KCs, which create KCs to hyperproliferate and also altered differentiation. Thus, the establishment of mutual KC-immunocyte stimulation (KC activation cycle) will leads to psoriasis [7, 8]. The hyperproliferation in psoriasis seemed to result from an increase in the number of transit amplifying cells, following depletion of the stem cell compartment [9]. As a whole, these changes suggest that intermediate filament (IF) keratin pair provides specific functional requirements to maintain epidermal KCs. KCs stability and integrity are mainly depend on keratin proteins [10, 11]. Keratins are the main structural cytoskeletal protein, an IF in all epithelia [12]. In normal skin, basal KCs express K5 and Keratin 14 (K14) keratins which helps in proliferation, whereas suprabasal cells express K1 and Keratin 10 (K10) keratins which supports differentiation process [13, 14]. Subsequently, any defects in these keratins can lead to cell fragility and are linked to a wide array of genodermatoses and cancers [15, 16].

Since genome-wide association studies (GWAS), connecting the psoriasis to the late cornified envelope gene cluster has specified that epidermal abnormalities along with hyperproliferative keratin pattern plays a major role in the pathogenesis of psoriasis [17, 18]. Studies have shown that dysfunction or mutations of keratin proteins are associated with a remarkable variety of skin disorders, such as skin blistering, inflammatory disorders and skin tumors [19]. The main aim of psoriasis treatments is to stop skin cells from growing so quickly and to remove scales. Methotrexate (MTX) is considered as the gold standard therapy for moderate to severe psoriasis [20–23]. Mostly, MTX exerts various immunomodulatory effects on T cell and also control KC growth [24]. In psoriasis, MTX was found to decreases the markers involved in hyperproliferation [25].

In this chapter we will first describe KC hyperproliferation then how keratins are expressed and regulated in psoriasis, then we will describe how MTX exert its action on controlling psoriasis through its immunomodulatory effect on Keratins and KC activation.

*Immunomodulatory Effect of Methotrexate Abruptly Controls Keratinocyte Activation in Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102811*

**Figure 1.**

*Illustration of the epidermal layers of the normal skin and psoriatic skin including scaliness, hyperkeratosis, and neutrophil accumulation in the stratum corneum. A indicates immunohistology of normal skin, B indicates immunohistology of psoriatic skin.*
