Inhibition of interleukin-2-inducible T-cell kinase causes reduction in imiquimod-induced psoriasiform inflammation through reduction of Th17 cells and enhancement of Treg cells in mice.

Abstract

Psoriasis is a debilitating chronic skin disease with a worldwide prevalence. Its main features include well-marked silvery scales on the skin of hands and feet and back which arise due to hyperproliferation of keratinocytes and infiltration of immune cells in the skin. Multiple interactions exist between adaptive immune cells such as T cells and innate immune cells such as neutrophils and macrophages which are key players in the pathogenesis of psoriasis. Interleukin-2-inducible T-cell kinase (ITK) plays a key role in Th17 cell development through control of several transcription factors. ITK has been shown to control NFATc1, NFkB and STAT3 in CD4+ T cells. Effect of ITK inhibitor in imiquimod (IMQ)-induced psoriasiform inflammation remains to be explored. In the current examination, role of ITK signaling and its inhibition blockade were evaluated on NFATc1, NFkB and STAT3, IL-17A, TNF-α, IFN-γ, Foxp3, IL-10 in CD4+ T cells in IMQ model. Our data display that ITK signaling is involved in IMQ-induced psoriatic inflammation as paralleled by enhancement of p-ITK, NFATc1, p-NFkB and p-STAT3 in CD4+ T cells. It was associated with enhancement of Th17/Th1 cells and neutrophilic inflammation in the skin. Preventive treatment with ITK inhibitor led to a reduction in Th17/Th1 cells and enhancement of Treg cells. Overall, this study suggests that ITK signaling is an important modulator of transcription factor signaling in CD4+ T cells which is associated with Th17/Th1 cells and psoriasiform inflammation in mice. ITK signaling blockade could be a therapeutic target for the treatment of psoriatic inflammation.

• Authors: Ahmed Nadeem, Sheikh F Ahmad, Naif O Al-Harbi, Khalid E Ibrahim, Faleh Alqahtani, Homood M As Sobeai, Moureq R Alotaibi
• Journal: Biochimie (Biochimie) Vol. 179 Pg. 146-156 (Dec 2020) ISSN: 1638-6183 [Electronic] France
• PMID: 33007409 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Chemical References

• Il17a protein, mouse
• Interleukin-17
• Tnf protein, mouse
• Tumor Necrosis Factor-alpha
• Protein-Tyrosine Kinases
• emt protein-tyrosine kinase
• Imiquimod

Topics

• Animals
• Disease Models, Animal
• Imiquimod (toxicity)
• Inflammation (drug therapy, immunology, metabolism, pathology)
• Interleukin-17 (metabolism)
• Intraepithelial Lymphocytes (drug effects)
• Male
• Mice, Inbred C57BL
• Protein-Tyrosine Kinases (antagonists & inhibitors, physiology)
• Psoriasis (drug therapy, immunology, metabolism, pathology)
• Signal Transduction (drug effects)
• Skin (immunology)
• T-Lymphocytes, Regulatory (drug effects)
• Th1 Cells (drug effects)
• Th17 Cells (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)