Apilimod Inhibits the Production of IL-12 and IL-23 and Reduces Dendritic Cell Infiltration in Psoriasis

Abstract

Psoriasis is characterized by hyperplasia of the epidermis and infiltration of leukocytes into both the dermis and epidermis. IL-23, a key cytokine that induces T H 17 cells, has been found to play a critical role in the pathogenesis of psoriasis. Apilimod is a small-molecule compound that selectively suppresses synthesis of IL-12 and IL-23. An open-label clinical study of oral administration of apilimod was conducted in patients with psoriasis. Substantial improvements in histology and clinical measurements were observed in patients receiving 70mg QD. The expression of IL-23p19 and IL-12/IL-23p40 in skin lesions was significantly reduced in this dose group, with a simultaneous increase in IL-10 observed. A decrease in the levels of T H 1 and T H 17 cytokines/chemokines in skin lesions followed these p19 and p40 changes. In parallel, a reduction in skin-infiltrating CD11c + dendritic cells and CD3 + T cells was seen, with a greater decrease in the CD11c + population. This was accompanied by increases in T and B cells, and decreases in neutrophils and eosinophils in the periphery. This study demonstrates the immunomodulatory activity of apilimod and provides clinical evidence supporting the inhibition of IL-12/IL-23 synthesis for the treatment of T H 1- and T H 17-mediated inflammatory diseases.

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

“…In this study, we have identified Langerin neg cDCs as the critical pathogenic DC population initiating psoriatic plaque formation in mice via production of IL-23. To this end, our data extend previous findings and provide a functional rational to interfere with IL-23 activity or production using, for example, Ustekinumab, Fumarate, or Apilimod (37)(38)(39). Moreover, our work suggests that future strategies specifically blocking IL-23 secretion by Langerin neg cDCs may provide an effective treatment for psoriasis avoiding the problems associated with the general immunosuppression seen in many therapeutic approaches today.…”

PIKfyve, a Class III Lipid Kinase, Is Required for TLR-Induced Type I IFN Production via Modulation of ATF3

“…PIKfyve-mediated PI(3,5)P 2 signaling has been shown to play a critical role in multiple biological processes by regulating endosomal trafficking, such as GLUT4 translocation, retroviral budding (12,13), autophagy (14), and neurodegeneration. Recently, we revealed that PIKfyve is the molecular target of apilimod (15), which is the first clinically evaluated small-molecule IL-12/IL-23 antagonist (16,17). We have shown that apilimod specifically binds to PIKfyve and inhibits its activity, which in turn silences TLR-induced IL-12/IL-23 production.…”

Insights into IL-23 biology: From structure to function

“…Apilimod which selectively suppresses the synthesis of IL-12 and IL-23 by impairing the nuclear accumulation of c-Rel is in clinical studies for psoriasis, Crohn's disease and RA [13,137].…”