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The Role of NLRP1, NLRP3, and AIM2 Inflammasomes In International Journal of Molecular Sciences Review The Role of NLRP1, NLRP3, and AIM2 Inflammasomes in Psoriasis: Review Magdalena Ci ˛azy˙ ´nska 1,* , Irmina Olejniczak-Staruch 2, Dorota Sobolewska-Sztychny 2, Joanna Narbutt 2, Małgorzata Skibi ´nska 2 and Aleksandra Lesiak 2 1 Nicolaus Copernicus Multidisciplinary Centre for Oncology and Traumatology, Department of Proliferative Diseases, 93-513 Lodz, Poland 2 Department of Dermatology, Pediatric Dermatology and Dermatological Oncology, Medical University of Lodz, 91-347 Lodz, Poland; [email protected] (I.O.-S.); [email protected] (D.S.-S.); [email protected] (J.N.); [email protected] (M.S.); [email protected] (A.L.) * Correspondence: [email protected]; Tel.: +48-660-726-304 Abstract: Inflammasomes are high-molecular-weight protein complexes that may cleave the two main proinflammatory cytokines, pro-interleukin-1β and pro-interleukin-18, into active forms, and contribute to psoriasis. Despite recent advances made in the pathogenesis of psoriasis, mainly studied as an autoimmune condition, activation of immune response triggers of psoriasis is still not completely understood. Recently, focus was placed on the role of inflammasomes in the pathogenesis of psoriasis. Multiple types of inhibitors and activators of various inflammasomes, inflammasome- related genes, and genetic susceptibility loci were recognized in psoriasis. In this systemic review, we collect recent and comprehensive evidence from the inflammasomes, NLRP1, NLRP3, and AIM2, in pathogenesis of psoriasis. Citation: Ci ˛azy´nska,M.;˙ Olejniczak-Staruch, I.; Keywords: psoriasis; inflammasomes; pathogenesis; NLRP1; NLRP3; AIM2 Sobolewska-Sztychny, D.; Narbutt, J.; Skibi´nska,M.; Lesiak, A. The Role of NLRP1, NLRP3, and AIM2 Inflammasomes in Psoriasis: Review. 1. Introduction Int. J. Mol. Sci. 2021, 22, 5898. Psoriasis is a chronic inflammatory skin disease that affects nearly 3% of the global https://doi.org/10.3390/ijms22115898 population. It is characterized by relapsing, red, scaly plaques and papules [1,2]; it may affect any part of the skin, but mostly occurs on the elbows, knees, and the scalp. Ap- Academic Editor: proximately 30% of patients with psoriasis develop seronegative psoriatic arthritis (PsA), GianLuca Moroncini usually manifesting as asymmetrical arthritis, which may involve entheses, joints, or even the spine [3]. In addition to psoriatic arthritis, psoriasis is increasingly recognized as a Received: 14 April 2021 multisystemic disease with metabolic syndrome, obesity, inflammatory bowel disease, Accepted: 28 May 2021 Published: 31 May 2021 cardiovascular disease, and depression (being the most common comorbidities) [4]. Psoriasis is a complex disease in which keratinocytes, immune cells, and other skin Publisher’s Note: MDPI stays neutral cells, including endothelial cells, interact dynamically [5]. Aberrant proliferation and ker- with regard to jurisdictional claims in atinocytes differentiation lead to epidermal hyperplasia and excessive dermal infiltration published maps and institutional affil- by numerous immune cells, including dendritic cells (DCs) and T cells. The increased iations. dermal capillary density and excessive production of several inflammatory chemokines and cytokines are the most important features of psoriasis [6]. The interaction between infiltrating immune cells and the keratinocytes observed in the disease is key to the devel- opment of an inflammatory response that is primarily mediated by interleukin (IL)-17 [7]. Although, IL-17, IL-23, and tumor necrosis factor (TNF) are recognized as main cytokines Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. involved in the development of psoriasis, more attention is paid to the role of the activation This article is an open access article of the multi-protein inflammasome complex in the pathogenesis of psoriasis, which in turn distributed under the terms and is associated with increased production of IL-1β and IL-18 [8–10]. conditions of the Creative Commons Inflammasomes consist of a group of cytosol protein complexes that play a crucial role Attribution (CC BY) license (https:// in the innate immune response, contributing to the host defense against pathogens and creativecommons.org/licenses/by/ repair processes upon the induction of inflammation [11]. Activation and assembly of the in- 4.0/). flammasome complex is mediated by damage-related molecular patterns (DAMP) or by the Int. J. Mol. Sci. 2021, 22, 5898. https://doi.org/10.3390/ijms22115898 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 5898 2 of 11 unrestrained release of pathogen-associated molecular patterns (PAMPs) through specific pattern recognition receptors (PRRs) [12]. Several types of inflammasomes are recognized, depending on the PRR type that is involved, including nucleotide-like receptors (NLR), RIG-like receptors absent in melanoma-like receptors 2 (AIM2), toll-like receptors (TLR), and pyrene. Assembly of the inflammasome components involves recognition inflamma- some receptor interaction with the apoptosis-associated speck-like protein, containing a caspase recruitment domain (ASC) and effector protein pro-caspase-1, -5, or -11 [13,14], which leads to the activation of the effector caspase through proteolytic cleavage. In the next step, the activated caspase-1 cleaves pro-IL-18 and pro-IL-1β, producing their active forms. It was reported that increasing IL-18 secretion promotes the maintenance and development of Th17 cells, which are broadly associated with autoimmune inflammatory diseases, such as psoriasis [15]. Moreover, psoriatic skin shows elevated caspase-1 and -5 activities [16]. Earlier studies also showed an increase in the level of IL-18 in psoriatic lesions, correlating meaningfully with the time of the disease and clinical severity [17,18]. Proinflammatory cy- tokines, secreted in large amounts, activate effector cells, including keratinocytes, macrophages, and neutrophils, which then induce an inflammatory response in damaged tissue. Therefore, abnormal and chronic activation of inflammasome complexes underlie the pathology of psoriasis due to the increased levels of pro-inflammatory cytokines. Previous studies confirmed the role of genetic components associated with the inflammasome in psoriasis susceptibility [19]. However, the accurate role of inflammasomes in psoriatic arthritis and psoriasis is still mainly undefined. This extensive systematic review presents the contributions of inflammasomes and immune cells to the pathogenesis of psoriatic arthritis and psoriasis. We conducted a review of the literature, investigating the role of inflammasomes and immune cells in the pathogenesis of psoriasis, using a systematic electronic literature search of the PubMed and Science Direct databases. The databases were searched using the terms “inflammasome”, “NLRP1”, “NLRP3” or “AIM2” and “psoriasis” or “psoriatic arthritis”. The search yielded 1612 citations. They were screened and 723 duplicate articles were removed. No exclusion criteria were defined. Using the selection criteria, 889 papers were reviewed by title and abstract and 774 were excluded. A further 115 studies were identified for full-text assessment and 98 papers were excluded. All articles, published until 1 March, 2021, were considered. Seventeen articles qualified for quality evaluation. They were positively assessed and included in this systematic review. The pertinence of each article was evaluated with an attentive and critical view regarding the type and content of the article and the impact factor of the publishing journal. Off-topic publications were eliminated. The study selection scheme is presented in Figure1. The characteristics of the included studies are summarized in Table1. Table 1. The inflammasome in psoriasis. Author Inflammasome Effector Signal Cell Type Mouse/Human Main Finding Cytosolic DNA can trigger AIM2 inflammasome IL-1β activation Dombrowski et al. [20] AIM2 IL-1β Keratinocytes Human in psoriasis; cathelicidin LL-37 interfered with DNA-sensing inflammasomes. NLRP1 inflammasome complex genetic Ekman et al. [16] NLRP1 IL-1β, IL-18 n/a Human variations are related to elevated vulnerability to psoriasis. CAG significantly reduced Dendritic cells, imiquimod-triggered NLRP3 Deng et al. [21] NLRP3 IL-1β Neutrophils, T Mouse inflammasome activation and gasdermin lymphocytes D (GSDMD)-mediated pyroptosis. Int. J. Mol. Sci. 2021, 22, 5898 3 of 11 Table 1. Cont. The expression of NLRP3 in psoriatic samples was 3.5 to 4.3 times higher than the expression of NLRP3 in normal skin IL-1β, Su et al. [22] NLRP3 Keratinocytes Human biopsy samples; NLRP3 expression is caspase 1 upregulated in psoriasis and is associated with concomitant accumulation of IL-1b and caspase 1. EGCG reduces AIM2-induced IL-1b secretion by suppressing IL 1b-mediated Yun et al. [23] AIM2 IL-1β HEKn Human priming and poly-induced ASC oligomerization. EFLA 945 attenuates IMQ-induced Chung et al. [24] AIM2 IL-1β, IL-18 Macrophages Human psoriasis-related proinflammatory responses; the inflammasome expression components Jiang et al. [9] AIM2 IL-1β, IL-18 n/a Mouse NLRP3 and AIM2 are reduced by antagonist treatment. NLRP1 inflammasome activation is Neutrophils, Walter et al. [25] NLRP1 IL-1β, IL-18 Mouse promoted by isostearic acid in Keratinocytes cultured keratinocytes. NLRP3 inflammasome is activated by Zhang et al. [26] NLRP3 IL-1β Keratinocytes Human CD100 in keratinocytes through binding to PLXNB2. miR-155 activates the NLRP3 Luo et al. [27] NLRP3 IL-1β, IL-18 Keratinocytes Mouse
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