The P2X7 receptor is not essential for development of imiquimod-induced psoriasis-like inflammation in mice

Abstract

Psoriasis is a chronic inflammatory skin disorder, characterised by epidermal hyperplasia (acanthosis) and leukocyte infiltration of the skin. Current therapies are inadequate, highlighting the need for new therapeutic targets. The P2X7 receptor is implicated in the pathogenesis of psoriasis. This study investigated the role of P2X7 in imiquimod (IMQ)-induced psoriasis-like inflammation. Topically applied IMQ caused twofold greater ear swelling in BALB/c mice compared to C57BL/6 mice, which encode a partial loss-offunction missense mutation in the P2RX7 gene. However, there was no difference in histological skin pathology (acanthosis and leukocyte infiltration) between the two strains. IMQ treatment up-regulated P2X7 expression in skin from both mouse strains. Additionally, IMQ induced ATP release from cultured human keratinocytes, a process independent of cell death. Injection of the P2X7 antagonist Brilliant Blue G (BBG) but not A-804598 partly reduced ear swelling compared to vehicle-injected control mice. Neither antagonist altered skin pathology. Moreover, no difference in ear swelling or skin pathology was observed between C57BL/6 and P2X7 knock-out (KO) mice. Flow cytometric analysis of IMQtreated skin from C57BL/6 and P2X7 KO mice demonstrated similar leukocyte infiltration, including neutrophils, macrophages and T cells. In conclusion, this study demonstrates that P2X7 is not essential for development of IMQ-induced psoriasis-like inflammation but does not exclude a role for this receptor in psoriasis development in humans or other mouse models of this disease.

Extracellular ATP and IL-23 Form a Local Inflammatory Circuit Leading to the Development of a Neutrophil-Dependent Psoriasiform Dermatitis

“…For instance, contact hypersensitivity responses were inhibited in P2X7R −/− mice and potentiated in the presence of ATPγS, an ATP analog (Granstein et al, 2005, Weber et al, 2010). We and others have shown that P2X7R is highly upregulated in psoriatic lesions in both humans and mouse models (Geraghty et al, 2017, Killeen et al, 2013, Pastore et al, 2007). Finally, P2X7R signaling in a human ex vivo skin model provokes the expression of innate cutaneous inflammatory cytokines, DC17 differentiation, and Th17 responses (Killeen et al, 2013).…”

Long-term treatment with the P2X7 receptor antagonist Brilliant Blue G reduces liver inflammation in a humanized mouse model of graft-versus-host disease

“…This suggests long-term injections of saline may reduce some disease parameters in this humanized mouse model of GVHD. In support of this, injection of saline is used in other inflammatory disease models to rescue mice from weight loss [23,36].…”

“…Data is represented as the total number of cells measured per field of view. Epidermal thickness of skin sections was measured as described [23].…”

Purinergic Regulation of Neutrophil Function

“…Inhibition of P2X 3 R and P2X 2/3 R with a selective antagonist reduces rat neutrophil infiltration into stimulus-induced inflamed knee joints ( 53 ) but not skin and subcutaneous tissues ( 54 , 55 ). Similarly, P2X 7 R antagonism inhibits rat neutrophil infiltration into inflamed knee joints ( 56 ), but knockout of P2X 7 R has no effect on skin neutrophil infiltration ( 57 ). The variations between neutrophil infiltration in joints and skin tissues are probably caused by specific chemoattractants and the order of their action during neutrophil recruitment at different tissues ( 58 ).…”