TL1A/DR3 axis involvement in the inflammatory cytokine network during pulmonary sarcoidosis.

M Facco,F Calzetti,V Martini,S Carraro,N Tamassia,F Calabrese,F Cinetto,A Teramo,A Cabrelle,C Agostini,G Semenzato,M A Cassatella

doi:10.1186/s12948-015-0022-z

Abstract

BackgroundTNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place.MethodsIn this study, by flow cytometry, real-time PCR, confocal microscopy and immunohistochemistry analyses, TL1A and DR3 were investigated in the pulmonary cells and the peripheral blood of 43 patients affected by sarcoidosis in different phases of the disease (29 patients with active sarcoidosis, 14 with the inactive form) and in 8 control subjects.ResultsOur results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls. In patients with sarcoidosis TL1A was strongly more expressed in the lung than the blood, i.e., at the site of the involved organ. Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1.ConclusionsThese data suggest that TL1A/DR3 interactions are part of the extended and complex immune-inflammatory network that characterizes sarcoidosis during its active phase and may contribute to the pathogenesis and to the progression of the disease.

Highlights

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology characterized by a compartmentalization of CD4+ T helper 1 (Th1)/Th17 lymphocytes [1] and activated monocyte/macrophages in involved organs, predominantly the lungs [2, 3]
All subjects with active sarcoidosis showed a high intensity CD4+ lymphocytic alveolitis sustained by CD45RO+ T cells
CD4+ and CD8+ T cell subsets and Alveolar macrophages (AMs) detected in the bronchoalveolar lavage (BAL) of patients with inactive sarcoidosis were superimposable to those observed in controls (Table 2)

Summary

Introduction

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology characterized by a compartmentalization of CD4+ T helper 1 (Th1)/Th17 lymphocytes [1] and activated monocyte/macrophages in involved organs, predominantly the lungs [2, 3]. As a consequence of these effects, TL1A and its receptor are frequently involved in the pathogenesis of many autoimmune and inflammatory diseases, including rheumatoid arthritis [13, 14], psoriasis [15], and inflammatory bowel diseases [16, 17], most of them characterized by a Th1/ Th17 microenvironment as sarcoidosis [17,18,19]. TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place

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Results

Discussion

Conclusion