3, 3'- diindolylmethane hinders IL-17A/IL-17RA interaction and mitigates imiquimod-induced psoriasiform in mice.

Abstract

Psoriasis is a highly inflammatory autoimmune-mediated skin disease. The strongest evidence has pointed to the influential role of interleukin (IL) -17A in the aberrant pathology of psoriasis. Henceforth, targeting the IL-17A cytokine is of prime importance in controlling the disease severity of psoriasis. Reportedly, 3, 3'- diindolylmethane (DIM) is a phytochemical that alleviated acute atopic dermatitis. Howbeit, the therapeutic intervention of DIM against IL-17A/IL-17RA interaction and its signaling mediated pathogenesis in psoriasis remains unexplored. In the current report, we decoded the molecular basis of DIM in psoriasis. Docking analysis has reported that DIM identified an IL-17A binding region in the functional fibronectin-III-like domain of IL-17RA and abrogated IL-17A/IL-17RA interaction. In-vitro experiments demonstrated that DIM impeded IL-17A mediated hyper-proliferative phenotype of psoriatic-like keratinocytes. Furthermore, DIM abated the catabolic effects of IL-17A stimulated expression of pathogenic mediators like HMGB-1, Cyr-61, CCL-20, and VEGF via blunted activation of JAK/STAT pathway in psoriatic like keratinocytes. Profoundly, DIM restricted the reprogramming of psoriatic-like keratinocytes to overexpress IL-17RA in concert with IL-17A stimulation. In line with in-vitro studies, DIM also ameliorated skin lesions and epidermal hyperplasia in an imiquimod-induced mice model of psoriasis. Additionally, DIM also reduced STAT-3 phosphorylation and associated expression of Cyr-61, CCL-20, and VEGF in psoriatic mice. However, if DIM has a direct effect on STAT-3 inhibition or it negatively regulates STAT-3 function via blockade of IL-17A/IL-17RA interaction needs to be investigated in the future. Conclusively, our studies demonstrated that the blockade of IL-17A/IL-17RA interaction is a novel therapeutic perspective of DIM against the progression of psoriasis disease.

• Authors: Manupati Srikanth, Mahaboobkhan Rasool
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 109 Pg. 108795 (Aug 2022) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 35487087 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Indoles
• Interleukin-17
• STAT Transcription Factors
• Vascular Endothelial Growth Factor A
• Janus Kinases
• Imiquimod
• 3,3'-diindolylmethane

Topics

• Animals
• Dermatitis (pathology)
• Disease Models, Animal
• Imiquimod (pharmacology)
• Indoles
• Interleukin-17 (metabolism)
• Janus Kinases (metabolism)
• Keratinocytes
• Mice
• Psoriasis (chemically induced, drug therapy, genetics)
• STAT Transcription Factors (metabolism)
• Signal Transduction
• Skin (pathology)
• Vascular Endothelial Growth Factor A (metabolism)