Activation-dependent cell death of human monocytes is a novel mechanism of fine-tuning inflammation and autoimmunity

In patients with juvenile idiopathic arthritis (JIA), increased release of IFN-γ and GM-CSF in cells infiltrating synovial tissue can be a potent driver of monocyte activation. Given the fundamental role of monocyte activation in remodeling the early phases of inflammatory responses, here we analyze the GM-CSF/IFN-γ-induced activity of human monocytes in such a situation in vitro and in vivo. Monocytes from healthy donors were isolated and stimulated with GM-CSF±IFN-γ. Monocyte activation and death were analyzed by flow cytometry, immunofluorescence microscopy, ELISA and qPCR. T cell GM-CSF/IFN-γ expression and monocyte function were determined in synovial fluid and peripheral blood from 15 patients with active JIA and 21 healthy controls. Simultaneous treatment with GM-CSF and IFN-γ induces cell death of monocytes. This cell death is partly cathepsin B-associated and has morphological characteristics of necrosis. Monocytes responding to co-stimulation with strong pro-inflammatory activities are consequently eliminated. Monocytes surviving this form of hyper-activation retain normal cytokine production. Cathepsin B activity is increased in monocytes isolated from synovial fluid from patients with active arthritis. Our data suggest GM-CSF/IFN-γ-induced cell death of monocytes as a novel mechanism to eliminate overactivated monocytes thereby potentially balancing inflammation and autoimmunity in JIA.

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