title: Innate immune response of human alveolar macrophages during influenza A infection.
abstract: Alveolar macrophages (AM) are one of the key cell types for initiating inflammatory and immune responses to influenza virus in the lung. However, the genome-wide changes in response to influenza infection in AM have not been defined. We performed gene profiling of human AM in response to H1N1 influenza A virus PR/8 using Affymetrix HG-U133 Plus 2.0 chips and verified the changes at both mRNA and protein levels by real-time RT-PCR and ELISA. We confirmed the response with a contemporary H3N2 influenza virus A/New York/238/2005 (NY/238). To understand the local cellular response, we also evaluated the impact of paracrine factors on virus-induced chemokine and cytokine secretion. In addition, we investigated the changes in the expression of macrophage receptors and uptake of pathogens after PR/8 infection. Although macrophages fail to release a large amount of infectious virus, we observed a robust induction of type I and type III interferons and several cytokines and chemokines following influenza infection. CXCL9, 10, and 11 were the most highly induced chemokines by influenza infection. UV-inactivation abolished virus-induced cytokine and chemokine response, with the exception of CXCL10. The contemporary influenza virus NY/238 infection of AM induced a similar response as PR/8. Inhibition of TNF and/or IL-1β activity significantly decreased the secretion of the proinflammatory chemokines CCL5 and CXCL8 by over 50%. PR/8 infection also significantly decreased mRNA levels of macrophage receptors including C-type lectin domain family 7 member A (CLEC7A), macrophage scavenger receptor 1 (MSR1), and CD36, and reduced uptake of zymosan. In conclusion, influenza infection induced an extensive proinflammatory response in human AM. Targeting local components of innate immune response might provide a strategy for controlling influenza A infection-induced proinflammatory response in vivo.
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado, United States of America. wangj@njhealth.org
authors.forename: Jieru
authors.initials: J
authors.lastname: Wang
authors.forename: Mrinalini P
authors.initials: MP
authors.lastname: Nikrad
authors.forename: Emily A
authors.initials: EA
authors.lastname: Travanty
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Tzulip
authors.initials: T
authors.lastname: Phang
authors.forename: Bifeng
authors.initials: B
authors.lastname: Gao
authors.forename: Taylor
authors.initials: T
authors.lastname: Alford
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ito
authors.forename: Piruz
authors.initials: P
authors.lastname: Nahreini
authors.forename: Kevan
authors.initials: K
authors.lastname: Hartshorn
authors.forename: David
authors.initials: D
authors.lastname: Wentworth
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
mesh_terms: D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics*; D007251:Influenza, Human / Q000276:immunology*; D007700:Kinetics; D037181:Lectins, C-Type / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000821:virology*; D020411:Oligonucleotide Array Sequence Analysis; D010587:Phagocytosis; D011650:Pulmonary Alveoli / Q000276:immunology / Q000821:virology*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D000099181:Dectin-1
chemical_list: D018925:Chemokines; D016207:Cytokines; D037181:Lectins, C-Type; D000099181:Dectin-1