RESUMO
Over the last several decades, our understanding of regulated-cell-death (RCD) pathways has increased dramatically. In addition to apoptosis and accidental cell death (primary necrosis), a diverse spectrum of RCD pathways has been delineated. In the lung, airway macrophages are critical for maintaining the functionality of airways via the clearance of inhaled particles, cell debris, and infectious agents. Exposure of these cells to pathogenic organisms or particles can induce a variety of RCD pathways that promote the release of danger signals into the lung. These responses have evolved to trigger the innate and adaptive arms of the immune system and thus offer protection against pathogens; yet they can also contribute to the development of lung injury and pathogenic immune responses. In this review, we discuss recent studies that suggest a critical role for airway-macrophage RCD pathways in promoting the release of pulmonary danger signals in health and disease.
Assuntos
Alarminas/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Lesão Pulmonar/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Síndrome do Desconforto Respiratório/imunologia , Imunidade Adaptativa , Alarminas/genética , Animais , Apoptose/genética , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/genética , Citocinas/genética , Citocinas/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Pulmão/patologia , Lesão Pulmonar/genética , Lesão Pulmonar/patologia , Macrófagos Alveolares/patologia , Necrose/genética , Necrose/imunologia , Necrose/patologia , Piroptose/genética , Piroptose/imunologia , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/patologia , Transdução de SinaisRESUMO
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-α that boosted intracellular stores of IL-1α followed by caspase-8-dependent fragmentation of DNA. IL-1α 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-1α. In mice exposed to Be, TNF-α 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-α on AMs led to a break in peripheral tolerance. This potentially novel mechanism may underlie the known relationship between fine particle inhalation, TNF-α, and loss of peripheral tolerance in T cell-mediated autoimmune disease and hypersensitivities.