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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2024

Open Access 01-12-2024 | Gout | Research

Deficiency of histone deacetylases 3 in macrophage alleviates monosodium urate crystals-induced gouty inflammation in mice

Authors: Qi-Bin Yang, Meng-Yun Zhang, Liu Yang, Jie Wang, Qing-Sheng Mi, Jing-Guo Zhou

Published in: Arthritis Research & Therapy | Issue 1/2024

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Abstract

Background

Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs) can significantly reduce MSU crystals-induced inflammation. However, which one of HDACs members in response to MSU crystals was still unknown. Here, we investigated the roles of HDAC3 in MSU crystals-induced gouty inflammation.

Methods

Macrophage specific HDAC3 knockout (KO) mice were used to investigate inflammatory profiles of gout in mouse models in vivo, including ankle arthritis, foot pad arthritis and subcutaneous air pouch model. In the in vitro experiments, bone marrow-derived macrophages (BMDMs) from mice were treated with MSU crystals to assess cytokines, potential target gene and protein.

Results

Deficiency of HDAC3 in macrophage not only reduced MSU-induced foot pad and ankle joint swelling but also decreased neutrophils trafficking and IL-1β release in air pouch models. In addition, the levels of inflammatory genes related to TLR2/4/NF-κB/IL-6/STAT3 signaling pathway were significantly decreased in BMDMs from HDAC3 KO mice after MSU treatment. Moreover, RGFP966, selective inhibitor of HDAC3, inhibited IL-6 and TNF-α production in BMDMs treated with MSU crystals. Besides, HDAC3 deficiency shifted gene expression from pro-inflammatory macrophage (M1) to anti-inflammatory macrophage (M2) in BMDMs after MSU challenge.

Conclusions

Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout.
Appendix
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Literature
1.
Terkeltaub R. Update on gout: new therapeutic strategies and options. Nat Rev Rheumatol. 2010;6(1):30–8.PubMedCrossRef
2.
Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum. 2005;52(9):2936–46.PubMedCrossRef
3.
Scott P, Ma H, Viriyakosol S, Terkeltaub R, Liu-Bryan R. Engagement of CD14 mediates the inflammatory potential of monosodium urate crystals. J Immunol. 2006;177(9):6370–8.PubMedCrossRef
4.
Chen CJ, Shi Y, Hearn A, Fitzgerald K, Golenbock D, Reed G, Akira S, Rock KL. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Investig. 2006;116(8):2262–71.PubMedPubMedCentralCrossRef
5.
Qing YF, Zhang QB, Zhou JG, Jiang L. Changes in toll-like receptor (TLR)4-NFkappaB-IL1beta signaling in male gout patients might be involved in the pathogenesis of primary gouty arthritis. Rheumatol Int. 2014;34(2):213–20.PubMedCrossRef
6.
Harper JL. Out with gout: opening the door on acute inflammation. Immunol Cell Biol. 2010;88(1):13–4.PubMedCrossRef
7.
Busso N, So A. Mechanisms of inflammation in gout. Arthritis Res Therapy. 2010;12(2):206.CrossRef
8.
9.
Cleophas MC, Crisan TO, Lemmers H, Toenhake-Dijkstra H, Fossati G, Jansen TL, Dinarello CA, Netea MG, Joosten LA. Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases. Ann Rheum Dis. 2016;75(3):593–600.PubMedCrossRef
10.
Chen X, Barozzi I, Termanini A, Prosperini E, Recchiuti A, Dalli J, Mietton F, Matteoli G, Hiebert S, Natoli G. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc Natl Acad Sci USA. 2012;109(42):E2865–2874.PubMedPubMedCentralCrossRef
11.
Ziesche E, Kettner-Buhrow D, Weber A, Wittwer T, Jurida L, Soelch J, Muller H, Newel D, Kronich P, Schneider H, et al. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-kappaB. Nucleic Acids Res. 2013;41(1):90–109.PubMedCrossRef
12.
Mullican SE, Gaddis CA, Alenghat T, Nair MG, Giacomin PR, Everett LJ, Feng D, Steger DJ, Schug J, Artis D, et al. Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes Dev. 2011;25(23):2480–8.PubMedPubMedCentralCrossRef
13.
Clausen BE, Burkhardt C, Reith W, Renkawitz R, Forster I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 1999;8(4):265–77.PubMedCrossRef
14.
Yang QB, Li LQ, Zhang QB, He YL, Mi QS, Zhou JG. microRNA-223 Deficiency exacerbates Acute Inflammatory response to Monosodium Urate crystals by targeting NLRP3. J Inflamm Res. 2021;14:1845–58.PubMedPubMedCentralCrossRef
15.
Malvaez M, McQuown SC, Rogge GA, Astarabadi M, Jacques V, Carreiro S, Rusche JR, Wood MA. HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci USA. 2013;110(7):2647–52.PubMedPubMedCentralCrossRef
16.
Wells CE, Bhaskara S, Stengel KR, Zhao Y, Sirbu B, Chagot B, Cortez D, Khabele D, Chazin WJ, Cooper A, et al. Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. PLoS ONE. 2013;8(7):e68915.PubMedPubMedCentralCrossRef
17.
Medzhitov R, Horng T. Transcriptional control of the inflammatory response. Nat Rev Immunol. 2009;9(10):692–703.PubMedCrossRef
18.
Zhu H, Shan L, Schiller PW, Mai A, Peng T. Histone deacetylase-3 activation promotes tumor necrosis factor-alpha (TNF-alpha) expression in cardiomyocytes during lipopolysaccharide stimulation. J Biol Chem. 2010;285(13):9429–36.PubMedPubMedCentralCrossRef
19.
Hoeksema MA, Gijbels MJ, Van den Bossche J, van der Velden S, Sijm A, Neele AE, Seijkens T, Stoger JL, Meiler S, Boshuizen MC, et al. Targeting macrophage histone deacetylase 3 stabilizes atherosclerotic lesions. EMBO Mol Med. 2014;6(9):1124–32.PubMedPubMedCentralCrossRef
20.
Angiolilli C, Kabala PA, Grabiec AM, Van Baarsen IM, Ferguson BS, Garcia S, Malvar Fernandez B, McKinsey TA, Tak PP, Fossati G, et al. Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. Ann Rheum Dis. 2017;76(1):277–85.PubMedCrossRef
21.
Leus NG, van der Wouden PE, van den Bosch T, Hooghiemstra WT, Ourailidou ME, Kistemaker LE, Bischoff R, Gosens R, Haisma HJ, Dekker FJ. HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-kappaB p65 transcriptional activity. Biochem Pharmacol. 2016;108:58–74.PubMedPubMedCentralCrossRef
22.
Xia M, Zhao Q, Zhang H, Chen Y, Yuan Z, Xu Y, Zhang M. Proteomic Analysis of HDAC3 Selective Inhibitor in the Regulation of Inflammatory Response of Primary Microglia. Neural plasticity 2017, 2017:6237351.
23.
Sathishkumar C, Prabu P, Balakumar M, Lenin R, Prabhu D, Anjana RM, Mohan V, Balasubramanyam M. Augmentation of histone deacetylase 3 (HDAC3) epigenetic signature at the interface of proinflammation and insulin resistance in patients with type 2 diabetes. Clin Epigenetics. 2016;8:125.PubMedPubMedCentralCrossRef
24.
Martin WJ, Harper JL. Innate inflammation and resolution in acute gout. Immunol Cell Biol. 2010;88(1):15–9.PubMedCrossRef
25.
26.
Dhanasekar C, Kalaiselvan S, Rasool M. Morin, a Bioflavonoid suppresses Monosodium Urate Crystal-Induced Inflammatory Immune response in RAW 264.7 macrophages through the inhibition of Inflammatory mediators, intracellular ROS levels and NF-kappaB activation. PLoS ONE. 2015;10(12):e0145093.PubMedPubMedCentralCrossRef
27.
Kelly PN, Romero DL, Yang Y, Shaffer AL 3rd, Chaudhary D, Robinson S, Miao W, Rui L, Westlin WF, Kapeller R, et al. Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy. J Exp Med. 2015;212(13):2189–201.PubMedPubMedCentralCrossRef
28.
29.
Chen L, Hsieh MS, Ho HC, Liu YH, Chou DT, Tsai SH. Stimulation of inducible nitric oxide synthase by monosodium urate crystals in macrophages and expression of iNOS in gouty arthritis. Nitric Oxide: Biology Chem. 2004;11(3):228–36.CrossRef
30.
Tye H, Kennedy CL, Najdovska M, McLeod L, McCormack W, Hughes N, Dev A, Sievert W, Ooi CH, Ishikawa TO, et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell. 2012;22(4):466–78.PubMedCrossRef
31.
Yu P, Xiao L, Lin L, Tang L, Chen C, Wang F, Wang Y. STAT3-mediated TLR2/4 pathway upregulation in an IFN-gamma-induced Chlamydia trachomatis persistent infection model. Pathogens Disease 2016, 74(6).
32.
Melkamu T, Kita H, O’Grady SM. TLR3 activation evokes IL-6 secretion, autocrine regulation of Stat3 signaling and TLR2 expression in human bronchial epithelial cells. J cell Communication Signal. 2013;7(2):109–18.CrossRef
33.
Mouihate A, Mehdawi H. Toll-like receptor 4-mediated immune stress in pregnant rats activates STAT3 in the fetal brain: role of interleukin-6. Pediatr Res. 2016;79(5):781–7.PubMedCrossRef
34.
35.
Strippoli R, Carvello F, Scianaro R, De Pasquale L, Vivarelli M, Petrini S, Bracci-Laudiero L, De Benedetti F. Amplification of the response to toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome. Arthritis Rheum. 2012;64(5):1680–8.PubMedCrossRef
36.
Caiello I, Minnone G, Holzinger D, Vogl T, Prencipe G, Manzo A, De Benedetti F, Strippoli R. IL-6 amplifies TLR mediated cytokine and chemokine production: implications for the pathogenesis of rheumatic inflammatory diseases. PLoS ONE. 2014;9(10):e107886.PubMedPubMedCentralCrossRef
37.
Assier E, Boissier MC, Dayer JM. Interleukin-6: from identification of the cytokine to development of targeted treatments. Joint bone Spine. 2010;77(6):532–6.PubMedCrossRef
38.
Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, Yao Y. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2014;141(2):125–39.PubMedCrossRef
39.
Cavalcanti NG, Marques CD, Lins ELTU, Pereira MC, Rego MJ, Duarte AL, Pitta Ida R, Pitta MG. Cytokine Profile in gout: inflammation driven by IL-6 and IL-18? Immunol Investig. 2016;45(5):383–95.CrossRef
40.
Murakami Y, Akahoshi T, Kawai S, Inoue M, Kitasato H. Antiinflammatory effect of retrovirally transfected interleukin-10 on monosodium urate monohydrate crystal-induced acute inflammation in murine air pouches. Arthritis Rheum. 2002;46(9):2504–13.PubMedCrossRef
41.
Wang H, Lafdil F, Kong X, Gao B. Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target. Int J Biol Sci. 2011;7(5):536–50.PubMedPubMedCentralCrossRef
42.
Martin WJ, Walton M, Harper J. Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal-induced murine peritoneal model of acute gout. Arthritis Rheum. 2009;60(1):281–9.PubMedCrossRef
43.
Martin WJ, Shaw O, Liu X, Steiger S, Harper JL. Monosodium urate monohydrate crystal-recruited noninflammatory monocytes differentiate into M1-like proinflammatory macrophages in a peritoneal murine model of gout. Arthritis Rheum. 2011;63(5):1322–32.PubMedCrossRef
Metadata
Title
Deficiency of histone deacetylases 3 in macrophage alleviates monosodium urate crystals-induced gouty inflammation in mice
Authors
Qi-Bin Yang
Meng-Yun Zhang
Liu Yang
Jie Wang
Qing-Sheng Mi
Jing-Guo Zhou
Publication date
01-12-2024
Publisher
BioMed Central
Keywords
Gout
Cytokines
Published in
Arthritis Research & Therapy / Issue 1/2024
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-024-03335-4

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