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Elastase/LPS-exposed mice exhibit impaired innate immune responses to bacterial challenge: role of scavenger receptor A.

ABSTRACT: Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen associated with lower respiratory tract colonization and with acute exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). Why the immune system fails to eliminate NTHi and the exact contribution of the organism to COPD progression are not well understood, in part because we lack an animal model that mimics all aspects of COPD. For this study, we used an established murine model that exhibits typical features of COPD. Elastase/LPS-exposed mice infected with NTHi showed persistence of bacteria up to 5 days after infection, whereas mice exposed to elastase, LPS, or PBS cleared all bacteria by 3 days. Elastase/LPS-exposed mice also showed sustained lung neutrophilic inflammation, goblet cell metaplasia, airway hyperresponsiveness, and progression of emphysema at 15 days after infection. Alveolar macrophages isolated from elastase/LPS-exposed mice showed impaired bacterial phagocytosis, reduced expression of MARCO and of mannose receptor, and absent expression of scavenger receptor-A (SR-A). Neutralization of SR-A significantly decreased phagocytosis of NTHi by normal alveolar macrophages. Our results suggest that elastase/LPS-exposed mice show impaired bacterial clearance and sustained lung inflammation. Lack of SR-A expression may, in part, be responsible for impaired phagocytosis of bacteria by alveolar macrophages of elastase/LPS-exposed mice. These data validate the suitability of elastase/LPS model for investigating NTHi pathogenesis and progression of disease in COPD.

SUBMITTER: Ganesan S

PROVIDER: S-EPMC3338352 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Elastase/LPS-exposed mice exhibit impaired innate immune responses to bacterial challenge: role of scavenger receptor A.

Ganesan Shyamala S Faris Andrea N AN Comstock Adam T AT Sonstein Joanne J Curtis Jeffrey L JL Sajjan Uma S US

The American journal of pathology 20111108 1

Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen associated with lower respiratory tract colonization and with acute exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). Why the immune system fails to eliminate NTHi and the exact contribution of the organism to COPD progression are not well understood, in part because we lack an animal model that mimics all aspects of COPD. For this study, we used an established murine model that exhi ...[more]

PMID: 22079429

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Project description:IntroductionAccumulating data implicate the CD4+ T cell subset (Th17 cells) in rheumatoid arthritis (RA). IL-17 is an inflammatory cytokine that induces tumor necrosis factor (TNF)α, IL-1β and IL-6, all of which are targets of biologic therapies used to treat RA. RA patients are well documented to experience more infections than age-matched controls, and biologic therapies further increase the risk of infection. The Th17/IL-17 axis is vital for immunity to fungi, especially the commensal fungus Candida albicans. Therefore, we were prompted to examine the relationship between RA and susceptibility to C. albicans because of the increasing interest in Th17 cells and IL-17 in driving autoimmunity, and the advent of new biologics that target this pathway.MethodsWe analyzed peripheral blood and saliva from 48 RA and 33 healthy control subjects. To assess C. albicans-specific Th17 responses, PBMCs were co-cultured with heat-killed C. albicans extract, and IL-17A levels in conditioned supernatants were measured by ELISA. The frequency of Th17 and Th1 cells was determined by flow cytometry. As a measure of IL-17A-mediated effector responses, we evaluated C. albicans colonization rates in the oral cavity, salivary fungicidal activity and levels of the antimicrobial peptide β-defensin 2 (BD2) in saliva.ResultsCompared to controls, PBMCs from RA subjects exhibited elevated baseline production of IL-17A (P = 0.004), although they had similar capacity to produce IL-17A in response to Th17 cell differentiating cytokines (P = 0.91). However RA PBMCs secreted less IL-17A in response to C. albicans antigens (P = 0.006). Significantly more RA patients were colonized with C. albicans in the oral cavity than healthy subjects (P = 0.02). Concomitantly, RA saliva had reduced concentrations of salivary BD2 (P = 0.02). Nonetheless, salivary fungicidal activity was preserved in RA subjects (P = 0.70).ConclusionsRA subjects exhibit detectable impairments in oral immune responses to C. albicans, a strongly Th17-dependent opportunistic pathogen, despite an overall elevated baseline production of IL-17A.

Project description:The scavenger receptor MARCO is expressed in several subsets of naive tissue-resident macrophages and has been shown to participate in the recognition of various bacterial pathogens. However, the role of MARCO in antiviral defense is largely unexplored. Here, we investigated whether MARCO might be involved in the innate sensing of infection with adenovirus and recombinant adenoviral vectors by macrophages, which elicit vigorous immune responses in vivo Using cells derived from mice, we show that adenovirus infection is significantly more efficient in MARCO-positive alveolar macrophages (AMs) and in AM-like primary macrophage lines (Max Planck Institute cells) than in MARCO-negative bone marrow-derived macrophages. Using antibodies blocking ligand binding to MARCO, as well as gene-deficient and MARCO-transfected cells, we show that MARCO mediates the rapid adenovirus transduction of macrophages. By enhancing adenovirus infection, MARCO contributes to efficient innate virus recognition through the cytoplasmic DNA sensor cGAS. This leads to strong proinflammatory responses, including the production of interleukin-6 (IL-6), alpha/beta interferon, and mature IL-1α. These findings contribute to the understanding of viral pathogenesis in macrophages and may open new possibilities for the development of tools to influence the outcome of infection with adenovirus or adenovirus vectors.IMPORTANCE Macrophages play crucial roles in inflammation and defense against infection. Several macrophage subtypes have been identified with differing abilities to respond to infection with both natural adenoviruses and recombinant adenoviral vectors. Adenoviruses are important respiratory pathogens that elicit vigorous innate responses in vitro and in vivo The cell surface receptors mediating macrophage type-specific adenovirus sensing are largely unknown. The scavenger receptor MARCO is expressed on some subsets of naive tissue-resident macrophages, including lung alveolar macrophages. Its role in antiviral macrophage responses is largely unexplored. Here, we studied whether the differential expression of MARCO might contribute to the various susceptibilities of macrophage subtypes to adenovirus. We demonstrate that MARCO significantly enhances adenovirus infection and innate responses in macrophages. These results help to understand adenoviral pathogenesis and may open new possibilities to influence the outcome of infection with adenoviruses or adenovirus vectors.

Dataset Information

Elastase/LPS-exposed mice exhibit impaired innate immune responses to bacterial challenge: role of scavenger receptor A.

Publications

Elastase/LPS-exposed mice exhibit impaired innate immune responses to bacterial challenge: role of scavenger receptor A.

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