Impact of short and long amosite fibers on human macrophages, fibrosis and autoimmunity in mouse models

Abstract

Although epidemiological studies have suggested an association between asbestos exposure and systemic autoimmunity, the underlying mechanisms are poorly understood. Short asbestos fibers are often considered less harmful than long fibers but such a statement is still a matter of debates. This study aimed to compare the effects of short (SFA) and long (LFA) amosite fiber exposure on lung damage, autoimmunity and macrophage phenotype. Four months after lung exposure to 0.1 mg of fibers, BAL levels of lactate dehydrogenase, free DNA, CCL2, TIMP-1 and immunoglobulins A of LFA-exposed C57Bl/6 mice were increased when compared to fluids from control- and SFA-exposed mice. Effects in LFA-exposed mice were associated with lung fibrosis and autoimmunity including anti-double-strand DNA antibody production. Human monocyte-derived macrophages (MDMs) exposed to SFA or LFA at 20 µg/cm2 have a pro-inflammatory phenotype characterized by a significant increase of TNFα and IL-6 secretion. A decrease of efferocytosis capacities was also noted after SFA and LFA, whereas macrophage abilities to phagocyte fluorescent beads were unchanged when compared to control MDMs. SFA exposure induced IL-6 secretion and reduced the percentage of MDMs expressing MHCII and CD86 markers involved in antigen and T-lymphocyte stimulation. By contrast, NLRP3 inflammasome activation, evaluated through quantification of caspase-1 activity and IL-1β secretion is rather associated to LFA than SFA exposure. Our results demonstrated that only long-term exposure to LFA has induced significant lung damages and autoimmune effects supporting a worsened health effects of LFA in comparison to SFA.