Development of psoriasis by continuous neutrophil infiltration into the epidermis

Remarkable effects of anti-IL-17A and anti-IL-23 antibodies on psoriasis indicate deep involvement of IL-23/Th17 axis in the pathogenesis of psoriasis. According to the current immune theory, activation of dendritic cells initiates the generation of this axis. However, this theory is not enough to explain the mechanism, because the process of this activation is obscure and the antigen that is recognized by antigen-presenting cells and pathogenic T cells has long been unidentified. Therefore, I thought of another theory as follows. Neutrophils are attracted by LTB4 at subcorneal portion and infiltrate into the epidermis. At the time of neutrophil migration through the basement membrane, basal keratinocytes in G0/G1 phase enter the cell cycle and begin to proliferate, according to the principle, detachment-mediated cell proliferation. This passing is continuously repeated and leads to elongation of rete ridges. The IL-23/Th17 axis is generated by interactions between infiltrated neutrophils and keratinocytes. Briefly, neutrophils infiltrated into the epidermis secrete IL-17A, which acts on keratinocytes to express CCL20, a ligand for the chemokine receptor CCR6. Keratinocytes perturbed by neutrophil infiltration produce HSP70, followed by production of IL-23 via TLR4 using HSP70 as an endogenous ligand for TLR4. Natural Th17 cells expressing CCR6 are recruited to psoriatic epidermis and expand there in the presence of IL-23 and IL-1. In this manner, the framework of the IL-23/Th17 axis is created, which acts to maintain or exacerbate psoriasis. Noteworthy is the fact that this axis causes positive feedback loop, starting from IL-17A production by neutrophils and ending in IL-17A production by nTh17 cells. Therapeutic mechanisms of anti-IL-17A and anti-IL-23 antibodies, targeting neutrophils, were also described.