title: MyD88-dependent TLR4 signaling is selectively impaired in alveolar macrophages from asymptomatic HIV+ persons.
abstract: Alveolar macrophages (AMs) are the predominant effector cell in the lungs and contribute to a critical first line of defense against bacterial pathogens through recognition by pattern recognition receptors such as Toll-like receptor 4 (TLR4). TLR4-mediated tumor necrosis factor alpha (TNFalpha) release is significantly impaired in HIV(+) macrophages, but whether HIV impairs myeloid differentiation factor 88 (MyD88)-dependent and/or MyD-independent TLR4 signaling pathways in human macrophages is not known. Comparing human U937 macrophages with HIV(+) U1 macrophages (HIV-infected U937 subclone), the current study shows that HIV infection is associated with impaired macrophage TLR4-mediated signaling, specifically targeting the MyD88-dependent TLR4-mediated signaling pathway (reduced MyD88-interleukin-1 receptor-associated kinase [IRAK] interaction, IRAK phosphorylation, nuclear factor [NF]-kappaB nuclear translocation, and TNFalpha release) while preserving the MyD88-independent TLR4-mediated signaling pathway (preserved STAT1 phosphorylation, interferon regulatory factor [IRF] nuclear translocation, and interleukin-10 [IL-10] and RANTES release). Extracellular TLR4 signaling complex was intact (similar levels of CD14 and MD2), and similar patterns of response were observed in clinically relevant AMs from healthy and asymptomatic HIV(+) persons at high clinical risk of pneumonia. Taken together, these data support the concept that chronic HIV infection is associated with specific and targeted disruption of critical macrophage TLR4 signaling, which in turn may contribute to disease pathogenesis of bacterial pneumonia.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. stachado@bidmc.harvard.edu
authors.forename: Souvenir D
authors.initials: SD
authors.lastname: Tachado
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Medhavi
authors.initials: M
authors.lastname: Bole
authors.forename: Katharine
authors.initials: K
authors.lastname: Swan
authors.forename: Asha
authors.initials: A
authors.lastname: Anandaiah
authors.forename: Naimish R
authors.initials: NR
authors.lastname: Patel
authors.forename: Henry
authors.initials: H
authors.lastname: Koziel
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000276:immunology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006678:HIV; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000276:immunology / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism*; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism; D012306:Risk; D012307:Risk Factors; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D016207:Cytokines; D050835:Interferon Regulatory Factors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases