TRPA1 as a potential factor and drug target in scleroderma : dermal fibrosis and alternative macrophage activation are attenuated in TRPA1-deficient mice in bleomycin-induced experimental model of scleroderma

Background: Systemic sclerosis is a rheumatoid disease best known for its fibrotic skin manifestations called scleroderma. Alternatively activated (M2-type) macrophages are normally involved in the resolution of inflammation and wound healing but also in fibrosing diseases such as scleroderma. TRPA1 is a non-selective cation channel, activation of which causes pain and neurogenic inflammation. In the present study, we investigated the role of TRPA1 in bleomycin-induced skin fibrosis mimicking scleroderma. Methods: Wild type and TRPA1-deficient mice were challenged with intradermal bleomycin injections to induce a scleroderma-mimicking disease. Macrophages were investigated in vitro to evaluate the underlying mechanisms. Results: Bleomycin induced dermal thickening and collagen accumulation in wild type mice and that was significantly attenuated in TRPA1-deficient animals. Accordingly, the expression of collagens 1A1, 1A2, and 3A1 as well as pro-fibrotic factors TGF-beta, CTGF, fibronectin-1 and YKL-40, and M2 macrophage markers Arg1 and MRC1 were lower in TRPA1-deficient than wild type mice. Furthermore, bleomycin was discovered to significantly enhance M2-marker expression particularly in the presence of IL-4 in wild type macrophages in vitro, but not in macrophages harvested from TRPA1-deficient mice. IL-4-induced PPARγ-expression in macrophages was increased by bleomycin, providing a possible mechanism behind the phenomenon. Conclusions: In conclusion, the results indicate that interfering TRPA1 attenuates fibrotic and inflammatory responses in bleomycin-induced scleroderma. Therefore, TRPA1-blocking treatment could potentially alleviate M2 macrophage driven diseases like systemic sclerosis and scleroderma.publishedVersionPeer reviewe

Adipokines and Osteoarthritis: Novel Molecules Involved in the Pathogenesis and Progression of Disease

Obesity has been considered a risk factor for osteoarthritis and it is usually accepted that obesity contributes to the development and progression of osteoarthritis by increasing mechanical load of the joints. Nevertheless, recent advances in the physiology of white adipose tissue evidenced that fat cells produce a plethora of factors, called adipokines, which have a critical role in the development of ostearthritis, besides to mechanical effects. In this paper, we review the role of adipokines and highlight the cellular and molecular mechanisms at play in osteoarthritis elicited by adipokines. We also emphasize how defining the role of adipokines has broadned our understanding of the diversity of factors involved in the genesis and progression of osteoarthritis in the hope of modifying it to prevent and treat diseases

MKP-1 Deficiency Exacerbates Skin Fibrosis in a Mouse Model of Scleroderma

Scleroderma is a chronic fibrotic disease, where proinflammatory and profibrotic events precede collagen accumulation. MKP-1 [mitogen-activated protein kinase (MAPK) phosphatase-1] downregulates inflammatory MAPK pathways suppressing inflammation. MKP-1 also supports Th1 polarization, which could shift Th1/Th2 balance away from profibrotic Th2 profile prevalent in scleroderma. In the present study, we investigated the potential protective role of MKP-1 in scleroderma. We utilized bleomycin-induced dermal fibrosis model as a well-characterized experimental model of scleroderma. Dermal fibrosis and collagen deposition as well as the expression of inflammatory and profibrotic mediators were analyzed in the skin samples. Bleomycin-induced dermal thickness and lipodystrophy were increased in MKP-1-deficient mice. MKP-1 deficiency enhanced collagen accumulation and increased expression of collagens, 1A1 and 3A1, in the dermis. Bleomycin-treated skin from MKP-1-deficient mice also showed enhanced expression of inflammatory and profibrotic factors IL-6, TGF-β1, fibronectin-1 and YKL-40, and chemokines MCP-1, MIP-1α and MIP-2, as compared to wild-type mice. The results show, for the first time, that MKP-1 protects from bleomycin-induced dermal fibrosis, suggesting that MKP-1 favorably modifies inflammation and fibrotic processes that drive the pathogenesis of scleroderma. Compounds enhancing the expression or activity of MKP-1 could thus prevent fibrotic processes in scleroderma and possess potential as a novel immunomodulative drug.publishedVersionPeer reviewe

Leptin, a railroad switch enabling crossover signals among inflammation, immunity and metabolism

White adipose tissue is currently considered as an active endocrine organ that secretes a plethora of factors named adipokines, some of them being of pro-inflammatory nature that likely contribute to the low-level systemic inflammation, a status that is often present in metabolic syndrome-associated chronic pathologies such as obesity, type 2 diabetes, and atherosclerosis. Leptin is historically indisputably one of the most important adipokine secreted by fat cells, with a variety of physiological roles ranging from to the control of metabolism, energy homeostasis and inflammatory response to cognition. Leptin is also implicated in the connection between nutritional status and immune competence, modulating both the innate and adaptive immune responses in normal as well as pathological conditions. It has been shown that conditions characterized by low leptin levels are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of proinflammatory cytokines. Thus, leptin can be easily considered as a frank mediator of metabolic and inflammatory/immune responses.Adipobiology 2010; 2: 33-40

Beyond Fat Mass: Exploring the Role of Adipokines in Rheumatic Diseases

The cloning of leptin in 1994 by Zhang et al. introduced a novel concept about white adipose tissue (WAT) as a very dynamic organ that releases a plethora of immune and inflammatory mediators, such as adipokines and cytokines, which are involved in multiple diseases. Actually, adipokines exert potent modulatory actions on target tissues involved in rheumatic diseases including cartilage, synovial, bone and immune cells. The goal of this paper is to elucidate the recent findings concerning the involvement of adipokines in rheumatic diseases, such as rheumatoid arthritis (RA), osteoarthritis (OA), and systemic lupus erythematosus (SLE)

Adipokines, metabolic syndrome and rheumatic diseases

The metabolic syndrome (MetS) is a cluster of cardiometabolic disorders that result from the increasing prevalence of obesity. The major components of MetS include insulin resistance, central obesity, dyslipidemia, and hypertension. MetS identifies the central obesity with increased risk for cardiovascular diseases (CVDs) and type-2 diabetes mellitus (T2DM). Patients with rheumatic diseases, such as rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, and ankylosing spondylitis, have increased prevalence of CVDs. Moreover, CVD risk is increased when obesity is present in these patients. However, traditional cardiovascular risk factors do not completely explain the enhanced cardiovascular risk in this population. Thus, MetS and the altered secretion patterns of proinflammatory adipokines present in obesity could be the link between CVDs and rheumatic diseases. Furthermore, adipokines have been linked to the pathogenesis of MetS and its comorbidities through their effects on vascular function and inflammation. In the present paper, we review recent evidence of the role played by adipokines in the modulation of MetS in the general population, and in patients with rheumatic diseases

Dickkopf-3 (DKK3) Signaling in IL-1a-Challenged Chondrocytes: Involvement of the NF-?B Pathway

Objective: Osteoarthritis (OA) is an age-related biomechanical and low-grade inflammometabolic disease of the joints and one of the costliest and disabling forms of arthritis. Studies on matrix-degrading enzymes such as metalloproteases, which are implicated in the increased catabolism of extracellular matrix, are of paramount relevance. DKK3 is a member of DKK family and is best known for its role in cancer. Although there is some information about the participation of DKK3 in cartilage pathophysiology and on metalloproteases regulation, in particular, little is known about DKK3 signaling mechanisms. Thus, the aim of this study is to explore how DKK3 regulates matrix metalloproteinase-13 (MMP-13) expression. Design: Gene, protein expression and protein phosphorylation in primary human chondrocytes and ATDC5 mouse cells were assessed by RT-qPCR and Western blot analysis. Further studies on DKK3 activity were performed by targeting DKK3 gene with a specific siRNA. Results: DKK3 expression was found to be higher in OA human chondrocytes than healthy cells, being its expression decreased in interleukin-1? (IL-1?)-stimulated cells. DKK3 knockdown increased the induction of MMP-13 elicited by IL-1? in human and mouse chondrocytes and after the analysis of different signalling pathways, we observed that NF-?B pathway was involved in the regulation of MMP-13 expression by DKK3. Conclusions: Herein we have demonstrated, for the first time, that DKK3 gene silencing exacerbated NF-?B activation, resulting in an increased IL-1?-driven induction of MMP-13. Our results further confirm that DKK3 may play a protective role in OA by attenuating NF-?B activation and the subsequent production of metalloproteases.Funding: OG and FL are Staff Personnel of Xunta de Galicia (Servizo Galego de Saude, SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). JC is “Miguel Servet” Researcher “CP19/00172 (ISCIII/FEDER), MS and VF are currently “Sara Borrell” Researchers funded by ISCIII and FEDER (CD16/00111). RG is a “Miguel Servet” Researcher funded by Instituto de Salud Carlos III (ISCIII) and FEDER. CR is a predoctoral research scholar funded by ISCIII and FEDER (Exp. 18/00188). OG, RG, and MAGG are members of RETICS Programme, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III (ISCIII) and FEDER. FL is a member of CIBERCV (Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares). The work of OG and JP (PI17/00409), RG (PI16/01870 and CP15/00007) and FL (PI15/00681 PI18/00821 and CB16/11/00226) was funded by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of a project funded by Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (Project number 734899). OG is beneficiary of a project funded by Xunta de Galicia, Consellería de emprego e industria (GAIN) (IN607B2019/10). RG is beneficiary of a project funded by Mutua Madrileña 2018. AM wishes to acknowledge financial support from the European Structural and Social Funds through the Research Council of Lithuania (Lietuvos Mokslo Taryba) according to the activity ‘Improvement of researchers’ qualification by implementing world-class R&D projects’ of Measure No. 09.3.3-LMT-K-712 (grant application code: 09.3.3-LMT-K-712-01-0157, agreement No. DOTSUT-215) and the new funding programme: Attracting Foreign Researchers for Research Implementation (2018–2022)

The potential of lipocalin-2/NGAL as biomarker for inflammatory and metabolic diseases

Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is a secreted glycoprotein that belongs to a group of transporters of small lipophilic molecules in circulation. LCN2 has been recently characterized as an adipose-derived cytokine. This adipokine is believed to bind small substances, such as steroids and lipopolysaccharides, and has been reported to have roles in the induction of apoptosis in hematopoietic cells, transport of fatty acids and iron, modulation of inflammation, and metabolic homeostasis. Recently, LCN2 has emerged as a useful biomarker and rheumatic diseases. This review provides an overview of LCN2 in inflammation, immunity, and metabolism.Instituto de Salud Carlos III (ISCIII)Serivizo Galego de Saúde (SERGAS)Versus ArthritisDeanship of Scientific Research (DSR), King AbdulAziz UniversityXunta de Galicia/ESF (European Social Fund)Universidad de CoruñaGobierno de EspañaFundación IDIS-Ramón DomínguezRECTIS Programme/RIER/RD12/0009/0008ISCIII/PI14/00016ISCIII/PIE13/00024EU FP7/HEALTH.2012.2.4.5-2 305815Versus Arthritis/20194Deanship of Scientific Research (DSR), King AbdulAziz University/1-141/1434 HiCiComisión Europe