Myeloid related protein induces muscle derived inflammatory mediators in juvenile dermatomyositis

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

doi:10.1186/ar4311

Abstract

IntroductionThe 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.MethodsIn 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.ResultsSerum 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.ConclusionsThis 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.

Highlights

The aetiopathogenesis of juvenile dermatomyositis (JDM) remains poorly understood
Disease activity measures in JDM correlate with serum levels of MRP8/14 Serum levels of the heterodimer MRP8/14 were significantly higher in JDM patients compared to age-matched controls but did not vary according to drug treatment (Figure 1A, B)
MRP8/14 levels strongly correlated with validated clinical measures of disease activity (Figure 1B-E), including physician global assessment of disease activity (PGA, R = 0.65, P = 0.0003) and strength/stamina (CMAS, R = −0.55, P = 0.004), and only to a limited extent with disability assessment (CHAQ, R = 0.56, P = 0.062) and the muscle enzyme, creatine kinase (CK) (R = 0.4, P = 0.046)

Summary

Introduction

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 contribute to muscle pathology in JDM. Juvenile dermatomyositis (JDM) is a rare inflammatory disease of childhood affecting skin and muscle, frequently resulting in calcinosis, and sometimes with potentially life threatening complications including gut vasculitis and interstitial lung disease [1]. In JDM muscle, one of the earliest detectable the inflammatory process and in particular the myeloid cell infiltrate frequently seen early in myositis, or whether this is merely a secondary response to tissue necrosis. Our study identifies a novel pathway by which macrophage-muscle crosstalk can perpetuate inflammatory myositis

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Conclusion