IMQ‐induced skin inflammation in mice is dependent on IL‐1R1 and MyD88 signaling but independent of the NLRP3 inflammasome

Abstract

Keywords: IL-1R r Imiquimod r MyD88 r NLRP3 inflammasome r Skin inflammation Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Franck Morel e-mail: f.morel@univ-poitiers.fr IntroductionPsoriasis is a chronic inflammatory skin disease estimated to affect 2-3% of the general population [1]. Clinical presentation is usually associated with red, scaly, and raised plaques. These are the C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2848 Hanitriniaina Rabeony et al. Eur. J. Immunol. 2015. 45: 2847-2857 consequences of a marked thickening of the epidermis due to an increased proliferation of keratinocytes (acanthosis), a retention of nuclei in the stratum corneum (parakeratosis) caused by alterations of keratinocyte differentiation leading to reduced or loss of the granular layer, and the presence of inflammatory cell infiltrates in the epidermis and dermis [2]. The inflammatory infiltrate is composed mainly of dendritic cells, macrophages and T cells in the dermis and neutrophils, with some T cells in the epidermis [3]. The combination of this infiltration and acanthosis contributes to the overall thickness of lesions. Therefore, the pathogenesis of psoriasis clearly results from a cross-talk between immune cells, keratinocytes, endothelial cells, and fibroblasts, with the release of growth factors, chemokines, and cytokines required for the induction and the maintenance of this disease [3,4]. An important role of the IL-23/IL-17/IL-22 axis in the induction of psoriasis has become evident, in which IL-23 secreted by some DC is responsible for the production of the Th17-related proinflammatory cytokines . IL-1 family members also play an important role in the regulation of the immune response and dysregulation of their expressions leads to tissue destruction and severe pathological effects, including skin diseases such as psoriasis [5,6]. Clearly, IL-1 is considered as a key player in the initiation and the maintenance of psoriasis by inducing Th17-cell maturation and downstream cytokine production [7,8]. IL-1α and IL-1β, the original members of IL-1 family, recognize IL-1 receptor type 1 (IL-1R1) which leads to the recruitment of the adaptor molecule MyD88 (adaptor protein shared by IL-1R and TLR signaling) and activate transcription factors NF-κB and AP1, whereas the binding of IL-1 receptor antagonist (IL-1Ra) to IL-1R1 totally blocks the biological activity of both proinflammatory molecules 9]. The mature secreted form of IL-1β requires engagement of the protein complexes termed inflammasomes. NLRP3 inflammasome includes the adaptor protein ASC (apoptosis-associated Speck-like protein containing a Caspase recruitment domain) necessary for the activation of the cysteine protease caspase-1, responsible for cleaving pro-IL-1β to mature IL-1β, whereas IL-1α is already biologically active and its processing requires the protease calpain [5]. In vitro studies showed that IL-1α or IL-1β induces the production of CCL...

Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

“…It is unclear why the results from Rabeony et al disagree with previously published results demonstrating reduced imiquimod cream-induced skin inflammation in caspase-1-deficient mice, or with our results with CP-456,773 in the present study (47). However, Rabeony et al (48) do demonstrate that IL-1a and IL-1b together contribute to dermatitis and that caspase-1 activity is upregulated in response to imiquimod cream in their model. Furthermore, it has been reported that the isostearic acid component of the imiquimod cream can activate NLRP1 inflammasome-dependent cleavage and release of IL-1b from human keratinocytes and that isostearic acid might contribute to inflammation (49).…”

“…Reduced skin inflammation and dermal thickness induced by imiquimod cream has been observed in caspase-1-deficient mice (47). However, in a recent publication from Rabeony et al (48), imiquimod cream-induced skin inflammation was not reduced in NLRP3-, caspase-1-, and ASC-deficient mice. It is unclear why the results from Rabeony et al disagree with previously published results demonstrating reduced imiquimod cream-induced skin inflammation in caspase-1-deficient mice, or with our results with CP-456,773 in the present study (47).…”

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

“…This previous study demonstrated that P2X7-mediated IL-1β release, which requires NLRP3 inflammasome activation [36], was essential for allergic contact dermatitis [35]. In contrast, activation of the NLRP3 inflammasome is not required for IMQ-induced psoriasis-like inflammation [37]. Thus, this provides a possible explanation as to why P2X7 is not essential in this model of psoriasis.…”

Oncostatin M overexpression induces skin inflammation but is not required in the mouse model of imiquimod‐induced psoriasis‐like inflammation

“…Other cytokines such as TNF-α, IL-1α/β, or IL-18 have been involved in the pathogenesis of psoriasis as well [8,9]. The contribution of these cytokines has been mainly studied using the standard mouse model of psoriasis-like skin inflammation induced by topical application of imiquimod (IMQ) [10][11][12][13]. Oncostatin M (OSM) has also been reported to be overexpressed in skin lesions of patients with psoriasis and shown to have proinflammatory activities in vitro on human primary keratinocytes and reconstituted epidermis [14].…”