Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 5/2013

Open Access 01-10-2013 | Research article

Myeloid related protein induces muscle derived inflammatory mediators in juvenile dermatomyositis

Authors: Kiran Nistala, Hemlata Varsani, Helmut Wittkowski, Thomas Vogl, Petra Krol, Vanita Shah, Kamel Mamchaoui, Paul A Brogan, Johannes Roth, Lucy R Wedderburn

Published in: Arthritis Research & Therapy | Issue 5/2013

Login to get access

Abstract

Introduction

The aetiopathogenesis of juvenile dermatomyositis (JDM) remains poorly understood. In particular the contribution of monocytes or macrophages, which are frequently observed to be an infiltrate within muscle tissue very early in the disease process, is unknown. We hypothesised that these cells secrete the pro-inflammatory myeloid related protein (MRP) 8/14 which may then contribute to muscle pathology in JDM.

Methods

In this study of 56 JDM patients, serum MRP8/14 levels were compared with clinical measures of disease activity. Muscle biopsies taken early in disease were assessed by immunohistochemistry to determine the frequency and identity of MRP-expressing cells. The effects of MRP stimulation and endoplasmic reticulum (ER) stress on muscle were tested in vitro. Serum or supernatant levels of cytokines were analyzed by multiplex immunoassay.

Results

Serum MRP8/14 correlated with physician’s global assessment of disease activity in JDM (R = 0.65, p = 0.0003) and muscle strength/endurance, childhood myositis assessment score (CMAS, R = −0.55, p = 0.004). MRP8/14 was widely expressed by CD68+ macrophages in JDM muscle tissue. When cultured with human myoblasts, MRP8 led to the secretion of MCP-1 and IL-6, which was enhanced by ER stress. Both inflammatory mediators were detected in significantly higher levels in the serum of JDM patients compared to healthy controls.

Conclusions

This study is the first to identify serum MRP8/14 as a potential biomarker for disease activity in JDM. We propose that tissue infiltrating macrophages secreting MRP8/14 may contribute to myositis, by driving the local production of cytokines directly from muscle.
Appendix
Available only for authorised users
Literature
1.
Wedderburn LR, Rider LG: Juvenile dermatomyositis: new developments in pathogenesis, assessment and treatment. Best Pract Res Clin Rheumatol. 2009, 23: 665-678. 10.1016/j.berh.2009.07.007.PubMedCentralCrossRefPubMed
2.
Gunawardena H, Wedderburn LR, North J, Betteridge Z, Dunphy J, Chinoy H, Davidson JE, Cooper RG, McHugh NJ: Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis. Rheumatology (Oxford). 2008, 47: 324-328.CrossRef
3.
Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, Foucat E, Dullaers M, Oh S, Sabzghabaei N, Lavecchio EM, Punaro M, Pascual V, Banchereau J, Ueno H: Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011, 34: 108-121. 10.1016/j.immuni.2010.12.012.PubMedCentralCrossRefPubMed
4.
Bilgic H, Ytterberg SR, Amin S, McNallan KT, Wilson JC, Koeuth T, Ellingson S, Newman B, Bauer JW, Peterson EJ, Baechler EC, Reed AM: Interleukin-6 and type I interferon-regulated genes and chemokines mark disease activity in dermatomyositis. Arthritis Rheum. 2009, 60: 3436-3446. 10.1002/art.24936.CrossRefPubMed
5.
Li CK, Varsani H, Holton JL, Gao B, Woo P, Wedderburn LR: MHC Class I overexpression on muscles in early juvenile dermatomyositis. J Rheumatol. 2004, 31: 605-609.PubMed
6.
Bartoccioni E, Gallucci S, Scuderi F, Ricci E, Servidei S, Broccolini A, Tonali P: MHC class I, MHC class II and intercellular adhesion molecule-1 (ICAM-1) expression in inflammatory myopathies. Clin Exp Immunol. 1994, 95: 166-172.PubMedCentralCrossRefPubMed
7.
Nagaraju K, Casciola-Rosen L, Lundberg I, Rawat R, Cutting S, Thapliyal R, Chang J, Dwivedi S, Mitsak M, Chen YW, Plotz P, Rosen A, Hoffman E, Raben N: Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum. 2005, 52: 1824-1835. 10.1002/art.21103.CrossRefPubMed
8.
Nagaraju K, Raben N, Loeffler L, Parker T, Rochon PJ, Lee E, Danning C, Wada R, Thompson C, Bahtiyar G, Craft J, Hooft Van Huijsduijnen R, Plotz P: Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies. Proc Natl Acad Sci USA. 2000, 97: 9209-9214. 10.1073/pnas.97.16.9209.PubMedCentralCrossRefPubMed
9.
Li CK, Knopp P, Moncrieffe H, Singh B, Shah S, Nagaraju K, Varsani H, Gao B, Wedderburn LR: Overexpression of MHC class I heavy chain protein in young skeletal muscle leads to severe myositis: implications for juvenile myositis. Am J Pathol. 2009, 175: 1030-1040. 10.2353/ajpath.2009.090196.PubMedCentralCrossRefPubMed
10.
Seeliger S, Vogl T, Engels IH, Schroder JM, Sorg C, Sunderkotter C, Roth J: Expression of calcium-binding proteins MRP8 and MRP14 in inflammatory muscle diseases. Am J Pathol. 2003, 163: 947-956. 10.1016/S0002-9440(10)63454-2.PubMedCentralCrossRefPubMed
11.
Loser K, Vogl T, Voskort M, Lueken A, Kupas V, Nacken W, Klenner L, Kuhn A, Foell D, Sorokin L, Luger TA, Roth J, Beissert S: The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells. Nat Med. 2010, 16: 713-717. 10.1038/nm.2150.CrossRefPubMed
12.
Hirono K, Foell D, Xing Y, Miyagawa-Tomita S, Ye F, Ahlmann M, Vogl T, Futatani T, Rui C, Yu X, Watanabe K, Wanatabe S, Tsubata S, Uese K, Hashimoto I, Ichida F, Nakazawa M, Roth J, Miyawaki T: Expression of myeloid-related protein-8 and −14 in patients with acute Kawasaki disease. J Am Coll Cardiol. 2006, 48: 1257-1264. 10.1016/j.jacc.2006.02.077.CrossRefPubMed
13.
Frosch M, Strey A, Vogl T, Wulffraat NM, Kuis W, Sunderkotter C, Harms E, Sorg C, Roth J: Myeloid-related proteins 8 and 14 are specifically secreted during interaction of phagocytes and activated endothelium and are useful markers for monitoring disease activity in pauciarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum. 2000, 43: 628-637. 10.1002/1529-0131(200003)43:3<628::AID-ANR20>3.0.CO;2-X.CrossRefPubMed
14.
Pilkington CA, Wedderburn LR: Paediatric idiopathic inflammatory muscle disease: recognition and management. Drugs. 2005, 65: 1355-1365. 10.2165/00003495-200565100-00004.CrossRefPubMed
15.
Martin N, Krol P, Smith S, Murray K, Pilkington CA, Davidson JE, Wedderburn LR: A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years’ experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies. Rheumatology (Oxford). 2011, 50: 137-145. 10.1093/rheumatology/keq261.CrossRef
16.
Bohan A, Peter JB: Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975, 292: 403-407. 10.1056/NEJM197502202920807.CrossRefPubMed
17.
Varsani H, Newton KR, Li CK, Harding B, Holton JL, Wedderburn LR: Quantification of normal range of inflammatory changes in morphologically normal pediatric muscle. Muscle Nerve. 2008, 37: 259-261. 10.1002/mus.20898.CrossRefPubMed
18.
Lovell DJ, Lindsley CB, Rennebohm RM, Ballinger SH, Bowyer SL, Giannini EH, Hicks JE, Levinson JE, Mier R, Pachman LM, Passo MH, Perez MD, Reed AM, Schikler KN, Smith M, Zemel LS, Rider LG: Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies. II. The Childhood Myositis Assessment Scale (CMAS): a quantitative tool for the evaluation of muscle function. The Juvenile Dermatomyositis Disease Activity Collaborative Study Group. Arthritis Rheum. 1999, 42: 2213-2219. 10.1002/1529-0131(199910)42:10<2213::AID-ANR25>3.0.CO;2-8.CrossRefPubMed
19.
Rider LG, Giannini EH, Harris-Love M, Joe G, Isenberg D, Pilkington C, Lachenbruch PA, Miller FW: Defining clinical improvement in adult and juvenile myositis. J Rheumatol. 2003, 30: 603-617.PubMed
20.
de Jager W, Prakken BJ, Bijlsma JW, Kuis W, Rijkers GT: Improved multiplex immunoassay performance in human plasma and synovial fluid following removal of interfering heterophilic antibodies. J Immunol Methods. 2005, 300: 124-135. 10.1016/j.jim.2005.03.009.CrossRefPubMed
21.
Wedderburn LR, Varsani H, Li CK, Newton KR, Amato AA, Banwell B, Bove KE, Corse AM, Emslie-Smith A, Harding B, Hoogendijk J, Lundberg IE, Marie S, Minetti C, Nennesmo I, Rushing EJ, Sewry C, Charman SC, Pilkington CA, Holton JL, UK Juvenile Dermatomyositis Research Group: International consensus on a proposed score system for muscle biopsy evaluation in patients with juvenile dermatomyositis: a tool for potential use in clinical trials. Arthritis Rheum. 2007, 57: 1192-1201. 10.1002/art.23012.CrossRefPubMed
22.
Zwadlo G, Schlegel R, Sorg C: A monoclonal antibody to a subset of human monocytes found only in the peripheral blood and inflammatory tissues. J Immunol. 1986, 137: 512-518.PubMed
23.
Roth J, Goebeler M, Erpenstein U, Sorg C: Differential regulation of the macrophage-specific surface antigen RM3/1 by cyclosporine, azathioprine, and dexamethasone. Transplantation. 1994, 57: 127-133. 10.1097/00007890-199401000-00020.CrossRefPubMed
24.
Zhu CH, Mouly V, Cooper RN, Mamchaoui K, Bigot A, Shay JW, Di Santo JP, Butler-Browne GS, Wright WE: Cellular senescence in human myoblasts is overcome by human telomerase reverse transcriptase and cyclin-dependent kinase 4: consequences in aging muscle and therapeutic strategies for muscular dystrophies. Aging Cell. 2007, 6: 515-523. 10.1111/j.1474-9726.2007.00306.x.CrossRefPubMed
25.
Vogl T, Leukert N, Barczyk K, Strupat K, Roth J: Biophysical characterization of S100A8 and S100A9 in the absence and presence of bivalent cations. Biochim Biophys Acta. 2006, 1763: 1298-1306. 10.1016/j.bbamcr.2006.08.028.CrossRefPubMed
26.
Price BD, Mannheim-Rodman LA, Calderwood SK: Brefeldin A, thapsigargin, and AIF4- stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis. J Cell Physiol. 1992, 152: 545-552. 10.1002/jcp.1041520314.CrossRefPubMed
27.
Liprandi A, Bartoli C, Figarella-Branger D, Pellissier JF, Lepidi H: Local expression of monocyte chemoattractant protein-1 (MCP-1) in idiopathic inflammatory myopathies. Acta Neuropathol. 1999, 97: 642-648. 10.1007/s004010051041.CrossRefPubMed
28.
Komohara Y, Hirahara J, Horikawa T, Kawamura K, Kiyota E, Sakashita N, Araki N, Takeya M: AM-3K, an anti-macrophage antibody, recognizes CD163, a molecule associated with an anti-inflammatory macrophage phenotype. J Histochem Cytochem. 2006, 54: 763-771. 10.1369/jhc.5A6871.2006.CrossRefPubMed
29.
Przybyla B, Gurley C, Harvey JF, Bearden E, Kortebein P, Evans WJ, Sullivan DH, Peterson CA, Dennis RA: Aging alters macrophage properties in human skeletal muscle both at rest and in response to acute resistance exercise. Exp Gerontol. 2006, 41: 320-327. 10.1016/j.exger.2005.12.007.CrossRefPubMed
30.
Nagaraju K, Raben N, Merritt G, Loeffler L, Kirk K, Plotz P: A variety of cytokines and immunologically relevant surface molecules are expressed by normal human skeletal muscle cells under proinflammatory stimuli. Clin Exp Immunol. 1998, 113: 407-414. 10.1046/j.1365-2249.1998.00664.x.PubMedCentralCrossRefPubMed
31.
Vattemi G, Engel WK, McFerrin J, Askanas V: Endoplasmic reticulum stress and unfolded protein response in inclusion body myositis muscle. Am J Pathol. 2004, 164: 1-7. 10.1016/S0002-9440(10)63089-1.PubMedCentralCrossRefPubMed
32.
Hirota M, Kitagaki M, Itagaki H, Aiba S: Quantitative measurement of spliced XBP1 mRNA as an indicator of endoplasmic reticulum stress. J Toxicol Sci. 2006, 31: 149-156. 10.2131/jts.31.149.CrossRefPubMed
33.
Martinon F, Chen X, Lee AH, Glimcher LH: TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010, 11: 411-418. 10.1038/ni.1857.PubMedCentralCrossRefPubMed
34.
Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS: Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004, 306: 457-461. 10.1126/science.1103160.CrossRefPubMed
35.
Vogl T, Tenbrock K, Ludwig S, Leukert N, Ehrhardt C, van Zoelen MA, Nacken W, Foell D, van der Poll T, Sorg C, Roth J: Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med. 2007, 13: 1042-1049. 10.1038/nm1638.CrossRefPubMed
36.
Tibble J, Teahon K, Thjodleifsson B, Roseth A, Sigthorsson G, Bridger S, Foster R, Sherwood R, Fagerhol M, Bjarnason I: A simple method for assessing intestinal inflammation in Crohn’s disease. Gut. 2000, 47: 506-513. 10.1136/gut.47.4.506.PubMedCentralCrossRefPubMed
37.
Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerss J, Stanevicha V, Mihaylova D, Ferriani V, Tsakalidou FK, Foeldvari I, Cuttica R, Gonzalez B, Ravelli A, Khubchandani R, Oliveira S, Armbrust W, Garay S, Vojinovic J, Norambuena X, Gamir ML, García-Consuegra J, Lepore L, Susic G, Corona F, Dolezalova P, Pistorio A, Martini A, Ruperto N, Roth J, Paediatric Rheumatology International Trials Organization (PRINTO): Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JAMA. 2010, 303: 1266-1273. 10.1001/jama.2010.375.CrossRefPubMed
38.
Salajegheh M, Kong SW, Pinkus JL, Walsh RJ, Liao A, Nazareno R, Amato AA, Krastins B, Morehouse C, Higgs BW, Jallal B, Yao Y, Sarracino DA, Parker KC, Greenberg SA: Interferon-stimulated gene 15 (ISG15) conjugates proteins in dermatomyositis muscle with perifascicular atrophy. Ann Neurol. 2010, 67: 53-63. 10.1002/ana.21805.PubMedCentralCrossRefPubMed
39.
Tezak Z, Hoffman EP, Lutz JL, Fedczyna TO, Stephan D, Bremer EG, Krasnoselska-Riz I, Kumar A, Pachman LM: Gene expression profiling in DQA1*0501+ children with untreated dermatomyositis: a novel model of pathogenesis. J Immunol. 2002, 168: 4154-4163.CrossRefPubMed
40.
Reed AM, Peterson E, Bilgic H, Ytterberg SR, Amin S, Hein MS, Crowson CS, Ernste F, Gillespie EB: Changes in novel biomarkers of disease activity in juvenile and adult dermatomyositis are sensitive biomarkers of disease course. Arthritis Rheum. 2012, 64: 4078-4086. 10.1002/art.34659.PubMedCentralCrossRefPubMed
41.
Banchereau J, Pascual V: Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity. 2006, 25: 383-392. 10.1016/j.immuni.2006.08.010.CrossRefPubMed
42.
Charo IF, Myers SJ, Herman A, Franci C, Connolly AJ, Coughlin SR: Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proc Natl Acad Sci USA. 1994, 91: 2752-2756. 10.1073/pnas.91.7.2752.PubMedCentralCrossRefPubMed
43.
De Paepe B, De Bleecker JL: Beta-chemokine receptor expression in idiopathic inflammatory myopathies. Muscle Nerve. 2005, 31: 621-627. 10.1002/mus.20294.CrossRefPubMed
44.
Delogu A, Schebesta A, Sun Q, Aschenbrenner K, Perlot T, Busslinger M: Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Immunity. 2006, 24: 269-281. 10.1016/j.immuni.2006.01.012.CrossRefPubMed
45.
Rulli NE, Rolph MS, Srikiatkhachorn A, Anantapreecha S, Guglielmotti A, Mahalingam S: Protection from arthritis and myositis in a mouse model of acute chikungunya virus disease by bindarit, an inhibitor of monocyte chemotactic protein-1 synthesis. J Infect Dis. 2011, 204: 1026-1030. 10.1093/infdis/jir470.CrossRefPubMed
46.
Tournadre A, Lenief V, Eljaafari A, Miossec P: Immature muscle precursors are a source of interferon-beta in myositis: role of Toll-like receptor 3 activation and contribution to HLA class I up-regulation. Arthritis Rheum. 2012, 64: 533-541.CrossRefPubMed
47.
Okiyama N, Sugihara T, Iwakura Y, Yokozeki H, Miyasaka N, Kohsaka H: Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A. Arthritis Rheum. 2009, 60: 2505-2512. 10.1002/art.24689.CrossRefPubMed
48.
Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neurath MF, Slattery T, Beach D, McClary J, Nagashima M, Morser J, Stern D, Schmidt AM: RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999, 97: 889-901. 10.1016/S0092-8674(00)80801-6.CrossRefPubMed
Metadata
Title
Myeloid related protein induces muscle derived inflammatory mediators in juvenile dermatomyositis
Authors
Kiran Nistala
Hemlata Varsani
Helmut Wittkowski
Thomas Vogl
Petra Krol
Vanita Shah
Kamel Mamchaoui
Paul A Brogan
Johannes Roth
Lucy R Wedderburn
Publication date
01-10-2013
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 5/2013
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar4311

Other articles of this Issue 5/2013

Arthritis Research & Therapy 5/2013 Go to the issue

Research article

Revisiting spatial distribution and biochemical composition of calcium-containing crystals in human osteoarthritic articular cartilage

Research article

Lack of change in urate deposition by dual-energy computed tomography among clinically stable patients with long-standing tophaceous gout: a prospective longitudinal study

Research article

Impact of extracellular matrix derived from osteoarthritis subchondral bone osteoblasts on osteocytes: role of integrinβ1 and focal adhesion kinase signaling cues

Editorial

How to regulate neutrophils in gout

Research article

GREM1, FRZB and DKK1 mRNA levels correlate with osteoarthritis and are regulated by osteoarthritis-associated factors

Commentary

A new paradigm of quality of care in rheumatoid arthritis: how our new therapeutics have changed the game
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits