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LRG1 Downregulation in Allergic Airway Disorders and Its Expression

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LRG1 Downregulation in Allergic Airway Disorders and Its Expression Hao et al. J Transl Med (2016) 14:202 DOI 10.1186/s12967-016-0929-2 Journal of Translational Medicine RESEARCH Open Access LRG1 downregulation in allergic airway disorders and its expression in peripheral blood and tissue cells Lijing Hao1,2†, Hua Xie3†, Bin Zhang2†, Dong Chen1, Shufen Wang1,2, Huiyun Zhang1 and Shaoheng He1* Abstract Background: Increased leucine-rich α2-glycoprotein-1 (LRG1) has been observed in plasma of individuals with vari- ous diseases. However, the role of LRG1 in allergic airway disease has not been investigated. Objective: To explore the involvement of LRG1 in allergy and its cell origins. Methods: The expression levels of LRG1 and its receptor transforming growth factor-beta receptor II (TGFBR2) in patients with allergic rhinitis (AR) and asthma (AS) were examined by flow cytometry, and enzyme-linked immuno- sorbent assay (ELISA). Results: LRG1 and soluble TGFBR2 expression in plasma of patients with AR and AS were markedly lower than that of healthy control (HC) subjects. Large proportions of CD123 HLA-DR , CD16 , CD4 , CD8 , CD14 , and CD19 cells expressed LRG1, although the percentages of LRG1 cells+ in these− cell populations+ + were lower+ in +AR and AS + patients. Up to 89.8 and 15.5 % of dispersed mast cells expressed+ LRG1 and TGFBR2. Moreover, allergen extract expo- sure significantly reduced LRG1 and TGFBR2 expression in the plasma and leukocytes of patients with AR and AS. Conclusions: Reduced LRG1 and TGFBR2 levels in patients with allergic airway disorders are likely caused by inhibi- tory actions of allergens in LRG1 producing cells. Thus, LRG1 may be a key regulatory factor of allergic responses. Keywords: LRG1, TGFBR2, Allergic airway disorder, Mast cells, Leukocytes Background LRG1 is expressed during haematopoiesis, especially LRG1 (HGNC: 29480) is a 50-kDa glycoprotein contain- during differentiation of the neutrophilic granulocyte ing 23 % carbohydrate by weight [1]. It consists of 312 lineage [5]. It also promotes neovascularization through amino acids, of which 66 are leucines. The predicted binding to the accessory receptor endoglin, and acti- secondary structure suggests that LRG1 may be a mem- vates transforming growth factor beta (TGF-β) signal- brane-associated or membrane-derived protein [2]. ling in endothelial cells via the TGFBR2 (HGNC: 11773) LRG1 belongs to the leucine-rich repeat protein family -ALK-1/Smad1/5/8 pathway [6]. Increased LRG1 levels [3], members of which are commonly involved in signal have been observed in serum or plasma of patients with transduction, cell adhesion, development, DNA repair, various types of cancers [7] including lung cancer [8]. It recombination, transcription, and RNA processing [4]. is suggested that LRG1 may be a useful marker of pediat- ric appendicitis as it was elevated in urine [9] and plasma [10] of children with acute appendicitis and enriched in diseased appendices. Because serum LRG concentrations *Correspondence: [email protected]; [email protected] correlate well with disease activity in ulcerative colitis †Lijing Hao, Hua Xie and Bin Zhang contributed equally to this work [11] and rheumatoid arthritis (RA) [12], this novel serum 1 Allergy and Clinical Immunology Research Centre, The First Affiliated biomarker could be a promising surrogate for C-reactive Hospital of Jinzhou Medical University, No. 2, Sect. 5, Renmin Street, Guta District, Jinzhou 121001, Liaoning, People’s Republic of China protein when monitoring disease progression in ulcera- Full list of author information is available at the end of the article tive colitis and RA. However, little is known regarding © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/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://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hao et al. J Transl Med (2016) 14:202 Page 2 of 15 the relationship between this unique glycoprotein and impact on asthma [16] and 2010 RA classification crite- allergic disorders. Since allergy is also an inflammatory ria [17], respectively. All patients were asked to stop tak- and immunological disease, and LRG may play a role in ing anti-allergy medication for at least 2 weeks prior to it, we investigated the expression of LRG1 in allergic dis- participating in the study. The recruited patients did not orders and its potential cell origins in the present study. have any airway infection for >1 month. Informed con- LRG1 is co-expressed with TGFBR2 and contains a sent was provided from each volunteer according to the putative membrane-binding region, thus suggesting declaration of Helsinki, and this study was approved by TGFBR2 as a potential cell-surface receptor for LRG1 the ethical committees of the First Affiliated Hospital of [13]. Elevated levels of TGFBR2 and LRG1 are observed Jinzhou Medical University. The general characteristics in the cerebrospinal fluid of patients with idiopathic of the patients and control subjects are summarized in normal pressure hydrocephalus (INPH) [14], suggest- Table 1. Peripheral venous blood sample was collected ing measuring TGFBR2 and LRG1expression levels may into K2EDTA anticoagulant containing tubes from each be useful for diagnosing INPH. However, the expression patient and HC subject, and were immediately processed levels of TGFBR2 in the plasma and blood cells under to collect cells and plasma for analysis. Human tonsillar allergic conditions remain uninvestigated. The aim of the specimen tissues were removed by tonsillectomy, after study is to investigate the expression levels of LRG1 and which dispersing mast cells and fibroblasts were col- its receptor TGFBR2 in the plasma and blood cells under lected. The protocol for the ethical use of human tissue allergic airway conditions. in research complied with the Declaration of Helsinki (2000) and was approved by the Committees of the First Methods Affiliated Hospital of Jinzhou Medical University. Reagents Type-I collagenase, and type-I hyaluronidase were pur- Cell line and culture chased from Sigma-Aldrich (St Louis, MO, USA). FACS A human mast cell line, HMC-1, was a gift from Dr. lysing solution and Cytofix/Cytoperm solution were Joseph H. Butterfield (Mayo Clinic, MN, USA). Cells obtained from BD Pharmingen (San Jose, CA, USA). A were cultured in RPMI 1640 medium supplemented with rabbit anti-human LRG1 antibody, a FITC-conjugated 10 % fetal bovine serum and 1 % penicillin and strepto- mouse anti-rabbit IgG antibody, and a PE-conjugated mycin in 75-cm2 tissue culture flasks (Falcon) at 37 °C in mouse anti-rabbit IgG antibody were purchased from a 5 % (v/v) CO2, water-saturated atmosphere. LifeSpan BioSciences (Seattle, WA, USA). PerCP-conju- gated mouse anti-human CD4, PE/Cy7-conjugated mouse Flow cytometric analysis of LRG1 and TGFBR2 expression anti-human CD8, APC/CY7-conjugated mouse anti- in white blood cells from patients exposed to allergens human CD14, APC-conjugated mouse anti-human CD19, To detect LRG1 and TGFBR2 expression on basophilic APC/Cy7-conjugated mouse anti-human CD16, PE/Cy7- granulocytes (CD123 + HLA-DR− cells) and neutro- conjugated mouse anti-human CD123, PerCP-conjugated phils (CD16+ cells), we added 4 antibodies (APC/CY7- mouse anti-human HLA-DR, PE/Cy7-conjugated mouse conjugated mouse anti-human CD16, PE/CY7-conjugated anti-human CD34, PerCP-conjugated mouse anti-human mouse anti-human CD123, PerCP-conjugated mouse anti- FcεR1, PE-conjugated mouse anti-human CD117, FITC- human HLA-DR, and PE-conjugated mouse anti-human conjugated mouse anti-human CD90, APC-conjugated TGFBR2) to 100 μl whole blood, and the cells were labelled mouse anti-human TGFBR2, and PE-conjugated mouse for 15 min, according to the manufacturer’s instructions. anti-human TGFBR2 antibodies were purchased from Following the ligation of red blood cells, white blood cells BioLegend (San Diego, CA, USA). Allergens for skin were fixed and permeabilized. The rabbit anti-human LRG1 prick tests were supplied by ALK-Abelló, Inc. (Denmark). antibody were added to 100 μl cell suspensions for 30 min Human LRG1, TGFBR2, and tryptase ELISA kits were at 4 °C, followed by staining with a FITC-conjugated mouse purchased from R&D Systems (Minneapolis, MN). Most anti-rabbit IgG antibody. To detect LRG1 and TGFBR2 general-purpose chemicals such as salts and buffer com- expression on monocytes (CD14+ cells), helper T cells ponents were of analytical grade. (CD4+ cells), cytotoxic T cells (CD8+ cells), and B cells (CD19+ cells), we stained cells with the following antibod- Patients and samples ies: PerCP-conjugated mouse anti-human CD4, PE/Cy7- A total of 16 AR, 15 AS, 5 combined AR and AS conjugated mouse anti-human CD8, APC/Cy7-conjugated (AR + AS), 8 RA and 15 HC subjects were recruited mouse anti-human CD14, and APC-conjugated mouse for the study. AS was diagnosed according to the crite- anti-human CD19. After washing, the cells were analysed ria of the Global Initiative for Asthma [15], and AR and on a fluorescence-activated cell sorting (FACS)Arial flow RA diagnosis were based on the allergic rhinitis and its cytometer with CellDevia software (BD Biosciences, USA). Hao et
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