MyD88-dependent TLR4 signaling is selectively impaired in alveolar macrophages from asymptomatic HIV+ persons

Abstract

IntroductionBacterial pneumonia remains a frequent and serious complication in asymptomatic HIV ϩ persons, despite relatively preserved peripheral blood CD4 ϩ T-lymphocyte counts 1 and use of highly active antiretroviral therapy (HAART) with undetectable plasma viral loads. 2 These persons have up to 25-fold greater risk of bacterial pneumonia than their healthy cohorts. 3 However, the mechanism contributing to this increased risk is not well understood. Toll-like receptor 4 (TLR4) represents a critical pattern recognition receptor in the innate immune host cell response to bacterial infection. Functional deficiency or genetic deletion of TLR 4 increases susceptibility to Haemophilus influenza, Streptococcus pneumoniae, and Klebsiella pneumoniae respiratory tract infections in murine models. 4,5 Another indication of its importance is that TLR4 polymorphisms are associated with increased susceptibility to lung infection. 6 Our laboratory has reported impaired TLR4-mediated tumor necrosis factor ␣ (TNF␣) release in alveolar macrophages from asymptomatic HIV ϩ persons at increased clinical risk of bacterial pneumonia. 7 Increased susceptibility may be in part related to reduced alveolar macrophage extracellular signalregulated kinase 1/2 (ERK1/2) mitogen-activated protein (MAP) kinase phosphorylation attributed to elevated MAP kinase phosphatase 1 (MKP-1) activity, 7 and constitutive phosphoinositol-3 kinase (PI3K) activation and heightened PI3K signaling in response to TLR4 activation. 8 These data suggest that the host cell proinflammatory cytokine may be suboptimal in the lungs of HIV ϩ persons and may in part contribute to increased bacterial pneumonia susceptibility and pathogenesis.TLR4 is the most studied of the TLR family of innate receptors. 9 It is a unique member of the TLR family of mammalian receptors in that TLR4 is capable of both adaptor molecule myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent signaling. 10-12 TLR4-mediated MyD88-dependent recognition of bacterial cell wall occurs at the cell surface, 11,13 does not require receptor internalization, 11 involves interleukin-1 receptorassociated kinase (IRAK) phosphorylation, and activation of TNF receptor-associated factor 6 (TRAF6), nuclear factor-B (NF-B), and MAP kinases (such as ERK1/2, p38, and Jun kinase), with the subsequent release of proinflammatory cytokines such as TNF␣ 14 that may contribute to an effective host defense response to bacteria. In contrast, TLR4-mediated MyD88-independent signaling requires receptor internalization and is mediated through Toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-␤ (IFN␤; TRIF), 11 involves activation of IFN regulatory factor 3 (IRF3) and STAT1 15 with release of type-1 IFNs, 16 IL-10, 15 RANTES 15 and may be involved in antiviral host defense. 17 Recent work in our laboratory has shown impaired TLR4-mediated signaling response in alveolar macrophages from asymptomatic HIV ϩ persons at high clinical risk of bacterial pneumonia. 7,8 However, whe...

Vitamin D Rescues Impaired Mycobacterium tuberculosis-Mediated Tumor Necrosis Factor Release in Macrophages of HIV-Seropositive Individuals through an Enhanced Toll-Like Receptor Signaling PathwayIn Vitro

“…Although 25D 3 levels were very low in BALF from HIV ϩ persons, especially from persons coinfected with M. tuberculosis, detailed clinical characteristics, a specific correlation with serum 1,25D 3 levels, and a correlation with macrophage function for individuals were not available. The use of human macrophage cell lines may not reflect the behavior of primary human macrophages, although the consistent finding of similar response patterns in human alveolar macrophages in both the current study (although the number of subjects was limited) and previous studies (7,27,46) validates these observations and supports the use of these human macrophage cell lines as an experimental model. Differences in the magnitude of observed biological responses in comparing HIV ϩ U1 macrophage cell lines and alveolar macrophages from HIV ϩ persons may in part reflect differences in the level of HIV infection (as 100% of U1 macrophages contain the HIV genome, whereas Ͻ10% of human alveolar macrophages contain the HIV genome) (7,28,33,34).…”

“…As a model for study of the influence of HIV infection on human macrophage function, experiments used the human monocyte U937 (American Type Culture Collection [ATCC]) and HIV-infected human monocyte U1 (subclone of U937; AIDS Research and Reference Reagent Program, Bethesda, MD) cell lines, as previously published (7,27,28). U1 cells contain two integrated copies of HIV-1 proviral DNA and are characterized by low levels of constitutive viral expression (29) that can be modulated with specific cytokines and phorbol myristate acetate (PMA) (30).…”

Epigenetic Regulation of Tumor Necrosis Factor α (TNFα) Release in Human Macrophages by HIV-1 Single-stranded RNA (ssRNA) Is Dependent on TLR8 Signaling

“…We investigated the role of endocytosis in HIV-1 ssRNA induction of TNF␣ release in macrophages in the presence or absence of an inhibitor of guanosine triphosphate (GTPase) dynamin (dynasore). This inhibitor suppressed endocytosis through suppression of TLR4-mediated MyD88-independent pathway signaling (24,25). Pretreatment of human macrophages with dynasore significantly reduced HIV-1 ssRNA-mediated TNF␣ release in THP-1 cells by ϳ50% ( Fig.…”

HIV-Associated Lung Infections and Complications in the Era of Combination Antiretroviral Therapy

“…Nonetheless, in asymptomatic HIV-infected patients, immune responses and signaling pathways may be abnormal even among those on ART (19). Risk for premature comorbidities, such as cardiovascular disease, renal, and liver disease, has been associated with residual inflammation and immunodeficiency despite treatment with ART (20).…”