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 Ahmed Nadeem a, * , Sheikh F. Ahmad a , Naif O. Al-Harbi a , Khalid E. Ibrahim b , Faleh Alqahtani a , Homood M. As Sobeai a , Moureq R. Alotaibi a a Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia b Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia article info Article history: Received 1 January 2020 Received in revised form 11 September 2020 Accepted 24 September 2020 Available online 29 September 2020 Keywords: Psoriasis Interleukin-2-inducible T-cell kinase Imiquimod Th17 cell Th1 cell Chronic disease 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 þ 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-a, IFN-g, Foxp3, IL-10 in CD4 þ 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 þ 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 þ 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. © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved. 1. Introduction Psoriasis is a chronic dermal inflammation affecting up to 3% of the world population. The most prevalent form of psoriasis is pla- que psoriasis that is identified by the presence of well- distinguished erythematous silvery plaques on extremities, scalp, and back. These plaques histologically consist of hyperproliferated keratinocytes with dysfunctional cornification, and infiltrated im- mune cells [1,2]. Immune cells of both innate and adaptive origin play a compelling role in the initiation, progression and amplifi- cation of psoriatic inflammation. Out of these immune cells, T cells are considered to be prominent players as they have the capacity to release various cytokines such as IL-17A, IL-22, IFN-g and TNF-a which affect proliferation/differentiation of keratinocytes in mul- tiple ways [3e5]. Th17/Th1 immune cell differentiation results from the effect of specific cytokines such as IL-12 and IL-23 on Th0 cells (naïve CD4 þ T cells) which are secreted by dendritic cells (DCs). Once differenti- ated, Th17 cells secrete IL-17A/IL-22 whereas Th1 secrete IFN-g/ TNF-a. Both Th17 and Th1 cells are believed to play a crucial role in proliferation/differentiation of keratinocytes through activation of multiple receptors that are expressed on them such as IL-17 re- ceptor and TNF-a receptor [4,6,7]. These observations are sup- ported by efficacy of already approved biologic therapies that target above mentioned pathways. For example, biologics inhibiting signaling of TNF-a, IL-17, IL-12/IL-23 are quite frequently used in psoriatic patients [2,8]. Recently, tyrosine kinase inhibitors have * Corresponding author. Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, PO Box 2455, Riyadh, 11451, Saudi Arabia. E-mail address: anadeem@ksu.edu.sa (A. Nadeem). Contents lists available at ScienceDirect Biochimie journal homepage: www.elsevier.com/locate/biochi https://doi.org/10.1016/j.biochi.2020.09.023 0300-9084/© 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved. Biochimie 179 (2020) 146e156