| First Author | Collins MK | Year | 2020 |
| Journal | JCI Insight | Volume | 5 |
| Issue | 9 | PubMed ID | 32255768 |
| Mgi Jnum | J:301921 | Mgi Id | MGI:6505360 |
| Doi | 10.1172/jci.insight.134356 | Citation | Collins MK, et al. (2020) A role for TNF-alpha in alveolar macrophage damage-associated molecular pattern release. JCI Insight 5(9) |
| abstractText | 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 in alveolar macrophages (AMs) and its impact on DAMP release. We found that phagocytosis of Be led to AM cell death independent of caspase, receptor-interacting protein kinases 1 and 3, or ROS activity. Before cell death, Be-exposed AMs secreted TNF-alpha that boosted intracellular stores of IL-1alpha followed by caspase-8-dependent fragmentation of DNA. IL-1alpha and nucleosomal DNA were subsequently released from AMs upon loss of plasma membrane integrity. In contrast, necrotic AMs released only unfragmented DNA and necroptotic AMs released only IL-1alpha. In mice exposed to Be, TNF-alpha promoted release of DAMPs and was required for the mobilization of immunogenic DCs, the expansion of Be-reactive CD4+ T cells, and pulmonary inflammation in a mouse model of CBD. Thus, early autocrine effects of particle-induced TNF-alpha on AMs led to a break in peripheral tolerance. This potentially novel mechanism may underlie the known relationship between fine particle inhalation, TNF-alpha, and loss of peripheral tolerance in T cell-mediated autoimmune disease and hypersensitivities. |
