title: SQSTM1/p62/A170 regulates the severity of Legionella pneumophila pneumonia by modulating inflammasome activity.
abstract: Sequestosome1/A170/p62 (SQSTM1) is a scaffold multifunctional protein involved in several cellular events, such as signal transduction, cell survival, cell death, and inflammation. SQSTM1 expression by macrophages is induced in response to environmental stresses; however, its role in macrophage-mediated host responses to environmental stimuli, such as infectious pathogens, remains unclear. In this study, we investigated the role of SQSTM1 in host responses to Legionella pneumophila, an intra-cellular pathogen that infects macrophages, in both an SQSTM1-deficient (SQSTM1(-/-) ) mouse model and macrophages from these mice. Compared with wild-type (WT) macrophages, the production and secretion of the proinflammatory cytokine IL-1β was significantly enhanced in SQSTM1(-/-) macrophages after infection with L. pneumophila. Inflammasome activity, indicated by the level of IL-18 and caspase-1 activity, was also elevated in SQSTM1(-/-) macrophages after infection with L. pneumophila. SQSTM1 may interact with nucleotide-binding oligomerization domain-like receptor family, caspase recruitment domain-containing 4 and nucleotide-binding oligomerization domain like receptor family, pyrin domain containing 3 proteins to inhibit their self-dimerization. Acute pulmonary inflammation induced by L. pneumophila and silica was enhanced in SQSTM1(-/-) mice with an increase in IL-1β levels in the bronchoalveolar lavage fluids. These findings suggest that SQSTM1 is a negative regulator of acute pulmonary inflammation, possibly by regulating inflammasome activity and subsequent proinflammatory cytokine production.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohtsuka
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishii
authors.forename: Masashi
authors.initials: M
authors.lastname: Matsuyama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ano
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morishima
authors.forename: Toru
authors.initials: T
authors.lastname: Yanagawa
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hizawa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology / Q000382:microbiology; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D054884:Host-Pathogen Interactions / Q000276:immunology; D015151:Immunoblotting; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D016952:Legionella pneumophila / Q000276:immunology* / Q000502:physiology; D007877:Legionnaires' Disease / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D000071456:Sequestosome-1 Protein; D012720:Severity of Illness Index
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D020170:Caspase 1
keywords: Inflammasome; Legionella; Macrophages; Pneumonia; Sequestosome1