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A role for TNFalpha in alveolar macrophage damange-associated molecular pattern release.

Morgan K. Collins,Abigail M Shotland,Morgan F Wade,Shaikh M. Atif,D. Richards,Manolo Torres-Llompart,D. Mack,Allison K. Martin,A. Fontenot,A. McKee

Published 2020 in JCI Insight

ABSTRACT

Chronic beryllium disease (CBD) is a metal hypersensitivity/autoimmune disease in which damage-associated molecular patterns (DAMPs) promote a break in T cell tolerance and expansion of Be2+/self-peptide reactive CD4+ T cells. In this study, we investigated the mechanism of cell death induced by beryllium particles (Be) in alveolar macrophages (AMΦs) and its impact on DAMP release. We found that phagocytosis of Be led to AM cell death independently of caspase, RIP1K, RIP3K or ROS activity. Prior to cell death, Be-exposed AMΦs secreted TNFalpha that boosted intracellular stores of IL-1alpha followed by caspase 8-dependent fragmentation of DNA. IL-1alpha and nucleosomal DNA were subsequently released from AMΦs upon loss of plasma membrane integrity. In contrast, necrotic AMs released only unfragmented DNA and necroptotic AMΦs released only IL-1alpha. In mice exposed to Be, TNFalpha promoted release of both DAMPs and was required for the mobilization of immunogenic DCs, expansion of Be-reactive CD4+ T cells and pulmonary inflammation in a mouse model of CBD. Thus, early autocrine effects of particle-induced TNFalpha on AMs led to a break in peripheral tolerance. This novel mechanism may underlie the known relationship between fine particle inhalation, TNFalpha and loss of peripheral tolerance in T cell-mediated autoimmune disease and hypersensitivities.

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