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The Expression of NOD2, NLRP3 and NLRC5 and Renal Injury in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

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The Expression of NOD2, NLRP3 and NLRC5 and Renal Injury in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis Wang et al. J Transl Med (2019) 17:197 https://doi.org/10.1186/s12967-019-1949-5 Journal of Translational Medicine RESEARCH Open Access The expression of NOD2, NLRP3 and NLRC5 and renal injury in anti-neutrophil cytoplasmic antibody-associated vasculitis Luo‑Yi Wang1,2,3, Xiao‑Jing Sun1,2,3, Min Chen1,2,3* and Ming‑Hui Zhao1,2,3,4 Abstract Background: Nucleotide‑binding oligomerization domain (NOD)‑like receptors (NLRs) are intracellular sensors of pathogens and molecules from damaged cells to regulate the infammatory response in the innate immune system. Emerging evidences suggested a potential role of NLRs in anti‑neutrophil cytoplasmic antibody (ANCA)‑associated vasculitis (AAV). This study aimed to investigate the expression of nucleotide‑binding oligomerization domain con‑ taining protein 2 (NOD2), NOD‑like receptor family pyrin domain containing 3 (NLRP3) and NOD‑like receptor family CARD domain containing 5 (NLRC5) in kidneys of AAV patients, and further explored their associations with clinical and pathological parameters. Methods: Thirty‑four AAV patients in active stage were recruited. Their renal specimens were processed with immu‑ nohistochemistry to assess the expression of three NLRs, and with double immunofuorescence to detect NLRs on intrinsic and infltrating cells. Analysis of gene expression was also adopted in cultured human podocytes. The associa‑ tions between expression of NLRs and clinicopathological parameters were analyzed. Results: The expression of NOD2, NLRP3 and NLRC5 was signifcantly higher in kidneys from AAV patients than those from normal controls, minimal change disease or class IV lupus nephritis. These NLRs co‑localized with podocytes and infltrating infammatory cells. The mean optical density of NOD2 in glomeruli was signifcantly higher in crescentic class than non‑crescentic class, and correlated with levels of proteinuria and serum creatinine at renal biopsy. The mean optical density of NLRC5 in glomeruli was signifcantly higher in crescentic class than non‑crescentic class, and correlated with proteinuria level, Birmingham Vasculitis Activity Score and the proportion of crescents in the renal specimen. Conclusions: The expression of three NLRs was upregulated in kidneys of AAV patients. The expression of NOD2 and NLRC5 was associated with the severity of renal lesions in AAV. Keywords: ANCA, NOD‑like receptors, Vasculitis Background polyangiitis (MPA) and eosinophilic granulomatosis with Anti-neutrophil cytoplasmic antibody (ANCA)-associ- polyangiitis (EGPA). ANCAs specifc for myeloperoxi- ated vasculitis (AAV) is a group of autoimmune diseases, dase (MPO) or proteinase 3 (PR3) are main pathogenic characterized by pauci-immune necrotizing crescen- autoantibodies in AAV [1]. tic glomerulonephritis in renal histology. AAV includes Accumulating evidences suggest that many constitu- granulomatosis with polyangiitis (GPA), microscopic ents of innate immune system, such as the complement system, play important roles in the pathogenesis of *Correspondence: [email protected] AAV [2–4]. Te pattern recognition receptor is another 1 Renal Division, Department of Medicine, Peking University First Hospital, critical component of the innate immune system as sen- Peking University Institute of Nephrology, No 8, Xishiku Street, Xicheng sors of exogenous pathogens and harmful molecules District, Beijing 100034, China Full list of author information is available at the end of the article [5]. As one of the most important components of the © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. J Transl Med (2019) 17:197 Page 2 of 11 germline-encoded recognition system, nucleotide- approved by the ethics committee of Peking University binding oligomerization domain (NOD)-like receptors First Hospital. (NLRs) participate in a number of infectious diseases, autoimmune diseases and kidney diseases [5–12]. Among Renal histopathology numerous NLRs, Te classic antimicrobic receptor Renal histopathology of AAV patients was evalu- nucleotide-binding oligomerization domain containing ated according to the standardized protocols [26–28] protein 2 (NOD2) showed enhanced pro-infammatory described previously. In brief, the lesions of glomeruli efects with PR3-ANCA in vitro [13, 14], and has been including fbrinoid necrosis, glomerulosclerosis and total reported to mediate the hyperglycemia-induced podo- crescents were calculated as afected percentage of the cyte dysfunction in diabetic nephropathy [15]. NOD-like total number of glomeruli in biopsies. Te lesions of tub- receptor family pyrin domain containing 3 (NLRP3) can ulointerstitium were semi-quantitatively scored accord- mediate the assembly of a cytosolic multiprotein com- ing to the afected area of tubulointerstitium: tubular plex called infammasome, and the subsequent IL-1β and atrophy, interstitial fbrosis (− for 0%, + for 0–50% IL-18 might be involved in AAV [16–19]. Besides NOD2 and ++ for > 50%) and interstitial infltration (− for and NLRP3, NOD-like receptor family CARD domain 0%, + for 0–25%, ++ for 25–50% and +++ for > 50%). containing 5 (NLRC5), the largest NLR, also participates Furthermore, each biopsy was classifed as focal, cres- in the developments of many kidney diseases including centic, mixed or sclerotic category, according to the ischemia–reperfusion injury and diabetic nephropathy pathologic classifcation system for ANCA-associated in various manners [20–24]. However, the role of NLRs glomerulonephritis proposed by Berden et al. [29]. remains largely unknown in AAV. Te aim of this study was to investigate the expression of NOD2, NLRP3 Assessment of NLR expression in kidneys and NLRC5 in kidneys of AAV patients, and further with immunohistochemistry explore their association with clinical and pathological Formaldehyde-fxed renal slides of AAV patients, nor- parameters. mal and disease controls were dewaxed in xylene ethanol at room temperature and rehydration through graded Methods ethanol. Antigen retrieval was then performed by heat- Patients and specimens ing the slides in citrate bufer (0.01 M, pH 6.0) in a pres- Tirty-four patients with active AAV receiving renal sure cooker at the highest pressure for 2 min and 30 s. biopsies before immunosuppressive therapy in Peking After cooled to room temperature and washed with PBS, University First Hospital from 2016 to 2018 were enrolled the slides were immersed in freshly prepared 3% hydro- in this study. All the patients met the criteria of the 2012 gen peroxide for 10 min at room temperature to quench Chapel Hill Consensus Conference defnition for AAV endogenous peroxidase activity. Non-specifc staining [1]. No patient had coexistence of other kidney dis- was blocked by incubating specimens with 3% bovine eases, secondary vasculitis, other autoimmune diseases serum albumin (BSA) in PBS at room temperature for or infections at the time of renal biopsy according to the 60 min. After the removal of blocking BSA without wash- clinical and laboratory data. Renal tissue from normal ing, primary antibodies for NOD2 (1:500, 20,980–1- parts of nephrectomized kidneys from seventeen patients AP; ProteinTech Group, Chicago, USA), NLRP3 (1:200, with solitary renal cell carcinoma was collected as normal ab214185; Abcam, Cambridge, UK) or NLRC5 (1:500, controls. Tey were identifed normal with regular light ab105411; Abcam, Cambridge, UK) were added and incu- microscopy, immunofuorescence and electron micros- bated overnight at 4 °C. For negative controls, specimens copy. Renal specimens from nineteen patients with mini- were incubated with 3% BSA instead of primary antibod- mal change disease (MCD) and twenty patients with class ies. Secondary antibodies (PV9001, ZSGB-Bio, Beijing, IV lupus nephritis (LN) according to the International China) were incubated with the specimens at 37 °C for Society of Nephrology/Renal Pathology Society (ISN/ 20 min. Sections were developed in fresh hydrogen per- RPS) [25] were collected as disease controls. Informed oxide plus 3–3′-diaminobenzidine tetra hydrochloride consent was signed by each participant. Tis research solution for 40 s. Nuclear staining was performed by was in compliance with the Declaration of Helsinki and incubating the specimens with haematoxylin for 8 min. Wang et al. J Transl Med (2019) 17:197 Page 3 of 11 Finally, the slides were dehydrated through ethanol and Scientifc, MA, USA) and insulin, transferrin, selenium, xylene and sealed with neutral gum. All the glomeruli in a ethanolamine solution (ITS, 41400045, Termo Fisher section at × 400 and at least 10 felds of tubulointerstitial Scientifc, MA, USA). To allow the cells to diferentiate, vision per kidney section at × 400 were observed blindly the cells were grown to 70–80% confuence, trypsinized for quantitative assessments of immunohistochemical and transferred at a dilution of 1:4 in growth media and staining. cultured at the non-permissive temperature of 37 °C (in Te staining results of NLRs were evaluated by the 5% CO2). After 14 days,
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