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

Nadeem, Ahmed; Ahmad, Sheikh F.; Al-Harbi, Naif O.; Ibrahim, Khalid E.; Alqahtani, Faleh; Sobeai, Homood M. As; Alotaibi, Moureq R.

doi:10.1016/j.biochi.2020.09.023

Cited by 36 publications

(30 citation statements)

References 56 publications

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“…Systemic TNF-a levels were also reduced following treatment. A separate study successfully showed that activation of STAT3 and NF-kB by upstream ITK was associated with upregulation of Th17 cells and increased neutrophilic inflammation of the skin in a murine model (Nadeem et al, 2020a). They additionally found that preventative treatment with an ITK inhibitor resulted in a reduction of Th17 cells and enhancement of Tregs.…”

Section: Psoriasismentioning

confidence: 98%

Targeting ITK signaling for T cell-mediated diseases

2021

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The focus of this review is to examine the role of ITK signaling in multiple diseases and investigate the clinical potential of ITK inhibition. The diseases and potential interventions reviewed include T cell-derived malignancies as well as other neoplastic diseases, allergic diseases such as asthma and atopic dermatitis, certain infectious diseases, several autoimmune disorders such as rheumatoid arthritis and psoriasis, and finally the use of ITK inhibition in both solid organ and bone marrow transplantation recipients.

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Section: Psoriasismentioning

confidence: 98%

Targeting ITK signaling for T cell-mediated diseases

2021

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“…They can release various cytokines, such as IL-17A, IL-22, IFN- γ , and TNF- α , which affect the proliferation/differentiation of keratinocytes in multiple ways ( Lowes et al, 2008 ; Ogawa et al, 2018 ). Bruton’s tyrosine kinase and interleukin-2-inducible T-cell kinase have the potential to become new therapeutic targets in treating psoriasis inflammation ( Nadeem et al, 2020a ; Nadeem et al, 2020b ). Proliferating cells use glycolysis with reduced mitochondrial oxidative phosphorylation for glucose metabolism, which provides cells with metabolic intermediates used in the duplication of cellular biomass during proliferation ( Lunt and Vander, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Kinase M2 Mediates Glycolysis Contributes to Psoriasis by Promoting Keratinocyte Proliferation

Liu

Dai

et al. 2021

Front. Pharmacol.

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Psoriasis is characterized by keratinocyte proliferation and immune cell infiltration. M2 isoform of pyruvate kinase (PKM2) was reported to have an important role in cell proliferation, which is a rate-limiting enzyme that regulates the final step of glycolysis. However, how PKM2 regulates cell metabolism and proliferation in psoriatic keratinocytes is still poorly understood. Interestingly, we found that PKM2 was highly expressed in psoriatic epidermis from patients and mouse models. PKM2 overexpression promoted keratinocyte glycolytic metabolism while knockdown inhibited keratinocyte proliferation and glycolysis. Mice lacking PKM2 specifically in keratinocytes, pharmacological inhibition of PKM2 or glycolysis inhibited keratinocyte proliferation and showed obvious remission in an imiquimod-induced psoriatic mouse model. Moreover, the inhibitor of the EGF-receptor blocked EGF-stimulated PKM2 expression and glycolysis in keratinocytes. We identify PKM2 as an upregulated gene in psoriasis. PKM2 is essential in keratinocyte over-proliferation and may represent a therapeutic target for psoriasis.

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“…In particular, DCs activated by TLR agonists reportedly induce Th17 differentiation and exacerbate autoimmune diseases (e.g., psoriasis and experimental autoimmune encephalomyelitis) (48,49). The mechanism by which IMQ-treated DCs induce Th17 differentiation in psoriatic inflammation has been clarified by recent studies (22,30,50). Although our study does not fully show the mechanism underlying the exacerbation of psoriasis through IMQ-induced DC activation, we have elucidated a portion of the mechanism underlying exacerbation of psoriasis by p32/C1qbp and mtROSdependent pathways.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Reactive Oxygen Species Are Essential for the Development of Psoriatic Inflammation

et al. 2021

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Psoriasis is a common immune-mediated, chronic, inflammatory skin disease that affects approximately 2–3% of the population worldwide. Although there is increasing evidence regarding the essential roles of the interleukin (IL)-23/IL-17 axis and dendritic cell (DC)-T cell crosstalk in the development of skin inflammation, the contributions of mitochondrial function to psoriasis are unclear. In a mouse model of imiquimod (IMQ)-induced psoriasiform skin inflammation, we found that hematopoietic cell-specific genetic deletion of p32/C1qbp, a regulator of mitochondrial protein synthesis and metabolism, protects mice from IMQ-induced psoriatic inflammation. Additionally, we demonstrate that p32/C1qbp is an important regulator of IMQ-induced DC activation, both in vivo and in vitro. We also found that p32/C1qbp-deficient DCs exhibited impaired production of IL-1β, IL-23, and mitochondrial reactive oxygen species (mtROS) after IMQ stimulation. Because the inhibition of mtROS suppressed IMQ-induced DC activation and psoriatic inflammation, we presume that p32/C1qbp and mtROS can serve as therapeutic targets in psoriasis.

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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

Cited by 36 publications

References 56 publications

Targeting ITK signaling for T cell-mediated diseases

Targeting ITK signaling for T cell-mediated diseases

Pyruvate Kinase M2 Mediates Glycolysis Contributes to Psoriasis by Promoting Keratinocyte Proliferation

Mitochondrial Reactive Oxygen Species Are Essential for the Development of Psoriatic Inflammation

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