Monocytes in sarcoidosis are potent TNF producers and predict disease outcome

Abstract

BackgroundPulmonary sarcoidosis is an inflammatory disease characterised by granuloma formation and heterogeneous clinical outcome. TNF is a proinflammatory cytokine contributing to granuloma formation and high levels of TNF have been shown to associate with progressive disease. Mononuclear phagocytes (MNPs) are potent producers of TNF and highly responsive to inflammation. In sarcoidosis, alveolar macrophages (AMs) have been well studied. However, MNPs also include monocytes/monocyte-derived cells and dendritic cells (DCs) that despite their central role in inflammation are poorly studied in sarcoidosis.ObjectiveTo determine the role of pulmonary monocyte-derived cells and DCs during sarcoidosis.MethodsWe performed in-depth phenotypic, functional and transcriptomic analysis of MNPs subsets from blood and bronchoalveolar lavage (BAL) fluid from 108 sarcoidosis patients and 30 healthy controls. We followed the clinical development of patients and assessed how the repertoire and function of MNP subsets at diagnosis correlated with 2-year disease outcome.ResultsMonocytes/monocyte-derived cells were increased in blood and BAL of sarcoidosis patients compared to healthy controls. Interestingly, high frequencies of blood intermediate monocytes at time of diagnosis associated with chronic disease development. RNAseq analysis showed highly inflammatory MNPs in BAL of sarcoidosis patients. Furthermore, frequencies of BAL monocytes/monocyte-derived cells producing TNF without exogenous stimulation at time of diagnosis increased in patients that were followed longitudinally. In contrast to AMs, the frequency of TNF producing BAL monocytes/monocyte-derived cells at time of diagnosis was highest in sarcoidosis patients that developed progressive disease.ConclusionOur data show that pulmonary monocytes/monocyte-derived cells are highly inflammatory and can be used as a predictor of disease outcome in sarcoidosis patients.