RRC ID 46359
Author Jessop F, Hamilton RF, Rhoderick JF, Shaw PK, Holian A.
Title Autophagy deficiency in macrophages enhances NLRP3 inflammasome activity and chronic lung disease following silica exposure.
Journal Toxicol Appl Pharmacol
Abstract Autophagy is an important metabolic mechanism that can promote cellular survival following injury. The specific contribution of autophagy to silica-induced inflammation and disease is not known. The objective of these studies was to determine the effects of silica exposure on the autophagic pathway in macrophages, as well as the general contribution of autophagy in macrophages to inflammation and disease. Silica exposure enhanced autophagic activity in vitro in Bone Marrow derived Macrophages and in vivo in Alveolar Macrophages isolated from silica-exposed mice. Impairment of autophagy in myeloid cells in vivo using Atg5(fl/fl)LysM-Cre(+) mice resulted in enhanced cytotoxicity and inflammation after silica exposure compared to littermate controls, including elevated IL-18 and the alarmin HMGB1 in the whole lavage fluid. Autophagy deficiency caused some spontaneous inflammation and disease. Greater silica-induced acute inflammation in Atg5(fl/fl)LysM-Cre(+) mice correlated with increased fibrosis and chronic lung disease. These studies demonstrate a critical role for autophagy in suppressing silica-induced cytotoxicity and inflammation in disease development. Furthermore, this data highlights the importance of basal autophagy in macrophages and other myeloid cells in maintaining lung homeostasis.
Volume 309
Pages 101-10
Published 2016-10-15
DOI 10.1016/j.taap.2016.08.029
PII S0041-008X(16)30252-6
PMID 27594529
PMC PMC5054752
MeSH Animals Autophagy* Female HMGB1 Protein / metabolism Lung / pathology Macrophages, Alveolar / drug effects* Macrophages, Alveolar / immunology Male Mice Mice, Transgenic NLR Family, Pyrin Domain-Containing 3 Protein / metabolism* Silicon Dioxide / toxicity*
IF 3.347
Times Cited 33
Mice RBRC02975