**3. Keratinocyte activation cycle (KAC)**

Basal KC have two alternative pathways to end up. In normal skin, KCs undergo proliferation in basal layer and differentiation in both spinosus, granular layer, finally it end up as anucleate corneocytes in cornified layers. During all these process, various factors like calcium, retinoic acid, vitamin D3 and protein kinase C (PKC) activators are required to induce proliferation and differentiation in epidermis [70–74]. For proliferation and differentiation, Epidermal KCs required a pair of kertain proteins, for instance, in normal skin Keratin pair K5/K14 expressed in basal layer and K1/K10 are expressed in spinosus layer [75].

However, in pathological conditions like epidermal injury, cancer and psoriasis an alternative KCs pathway is get activated by inflammatory mediators. This alternative pathway disturbed normal proliferation and migrating phenotype in KCs [76, 77]. This alternative pathway is considered as a unusual cycle formed by the interaction of KCs-immunocytes, which is precisely elucidated as KC activation cycle [78]. This activation cycle begins with leakage of interleukin-1 beta (IL-1 β) from KC after any injury or disease condition. This inflammatory mediator initiate activation of KCs by changing the keratin pattern from K5/14 to K6/16 and firmly maintained by TNF-α and TGF-α [60, 61, 75, 79]. After any treatment or lesional healing stage, IFN-γ was released by KCs which act as a signal for healing process and also induces the expression of K17 [69, 80]. To normalize the healed skin, a transforming growth factor-β (TGF-β) synthesized from dermal fibroblasts were found to aid KCs phenotype by producing K5/14 keratin in basal layer (**Figure 5**) [81].

#### **Figure 5.**

*The KC activation cycle. In normal KC, Basal layer produces K5 and K14 and differentiate to K1 and K10 with the help of ca2+, D3. Whereas in psoriatic KCs, K5 and K14 produce K6 and K16 by IL-1. TNF-α help to maintains activated KCs. Then, IFN-γ prompts K17 expression which stimulates KCs contractility. TGF-γ,a de-activating signal is not produced during psoriass, thereby hyperproliferation of epidermis in psoriasis. Symbol*  ↑ *indicates increase in psoriasis; symbol* ↓ *indicates decrease in psoriasis.*
