title: Myeloid related protein induces muscle derived inflammatory mediators in juvenile dermatomyositis.
abstract: BACKGROUND
  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.
authors.forename: Kiran
authors.initials: K
authors.lastname: Nistala
authors.forename: Hemlata
authors.initials: H
authors.lastname: Varsani
authors.forename: Helmut
authors.initials: H
authors.lastname: Wittkowski
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Petra
authors.initials: P
authors.lastname: Krol
authors.forename: Vanita
authors.initials: V
authors.lastname: Shah
authors.forename: Kamel
authors.initials: K
authors.lastname: Mamchaoui
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brogan
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Wedderburn
mesh_terms: D000293:Adolescent; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001706:Biopsy; D040501:Calgranulin A / Q000097:blood / Q000378:metabolism*; D040502:Calgranulin B / Q000097:blood / Q000378:metabolism*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003882:Dermatomyositis / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D053580:Muscle Strength; D009132:Muscles / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D040501:Calgranulin A; D040502:Calgranulin B; D018932:Chemokine CCL2; D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; C111835:CCL2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule