Identification of keratinocyte mitogens: implications for hyperproliferation in psoriasis and atopic dermatitis

ABSTRACT Psoriasis and atopic dermatitis (AD) are chronic inflammatory skin diseases characterized by keratinocyte hyperproliferation and epidermal acanthosis (hyperplasia). The milieu of disease-associated cytokines and soluble factors is considered a mitogenic factor, however, pinpointing the exact mitogens in this complex microenvironment is challenging. We employed organotypic human epidermal equivalents (HEEs), faithfully mimicking native epidermal proliferation and stratification, to evaluate the proliferative effects of a broad panel of (literature-based) potential mitogens. The keratinocyte growth factor molecule (KGF), the T-helper 2 (Th2) cytokines interleukin-4 (IL-4) and IL-13 and the psoriasis-associated cytokine IL-17A caused acanthosis by hyperplasia through a doubling in the number of proliferating keratinocytes. In contrast, IFN-γ lowered proliferation, while IL-6, IL-20, IL-22 and oncostatin M (OSM), induced acanthosis not by hyperproliferation but by hypertrophy. The Th2-cytokine mediated hyperproliferation was JAK/STAT3 dependent, while IL-17A and KGF induced MEK/ERK-dependent proliferation. This discovery that key regulators in AD and psoriasis are direct keratinocyte mitogens not only adds evidence to their crucial role in the pathophysiological processes but also highlights an additional therapeutic pillar for the mode of action of targeting biologicals (e.g., dupilumab) or small molecule drugs (e.g., tofacitinib) by the normalization of keratinocyte turnover within the epidermal compartment.