Decreased Alveolar Macrophage Apoptosis Is Associated with Increased Pulmonary Inflammation in a Murine Model of Pneumococcal Pneumonia

School of Medicine and Biomedical Sciences, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, United Kingdom.
The Journal of Immunology (Impact Factor: 4.92). 12/2006; 177(9):6480-8. DOI: 10.4049/jimmunol.177.9.6480
Source: PubMed

ABSTRACT Regulation of the inflammatory infiltrate is critical to the successful outcome of pneumonia. Alveolar macrophage apoptosis is a feature of pneumococcal infection and aids disease resolution. The host benefits of macrophage apoptosis during the innate response to bacterial infection are incompletely defined. Because NO is required for optimal macrophage apoptosis during pneumococcal infection, we have explored the role of macrophage apoptosis in regulating inflammatory responses during pneumococcal pneumonia, using inducible NO synthase (iNOS)-deficient mice. iNOS(-/-) mice demonstrated decreased numbers of apoptotic macrophages as compared with wild-type C57BL/6 mice following pneumococcal challenge, greater recruitment of neutrophils to the lung and enhanced expression of TNF-alpha. Pharmacologic inhibition of iNOS produced similar results. Greater pulmonary inflammation was associated with greater levels of early bacteremia, IL-6 production, lung inflammation, and mortality within the first 48 h in iNOS(-/-) mice. Labeled apoptotic alveolar macrophages were phagocytosed by resident macrophages in the lung and intratracheal instillation of exogenous apoptotic macrophages decreased neutrophil recruitment in iNOS(-/-) mice and decreased TNF-alpha mRNA in lungs and protein in bronchial alveolar lavage, as well as chemokines and cytokines including IL-6. These changes were associated with a lower probability of mice becoming bacteremic. This demonstrates the potential of apoptotic macrophages to down-regulate the inflammatory response and for the first time in vivo demonstrates that clearance of apoptotic macrophages decreases neutrophil recruitment and invasive bacterial disease during pneumonia.

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Available from: David H Dockrell, Sep 29, 2015
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    • "This observation, together with the known roles of macrophages, suggests macrophages may regulate inflammatory responses in the preterm lung [2]. This could derive from a number of the known roles of differentiated macrophages, alone or in combination, including the surface expression of death receptors ligands that may initiate apoptosis in vivo, the production of anti-inflammatory cytokines such as IL-10, or via efferocytosis and cell clearance [3], [4], [5], [6], [7]. "
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    ABSTRACT: BackgroundThe etiology of persistent lung inflammation in preterm infants with chronic lung disease of prematurity (CLD) is poorly characterized, hampering efforts to stratify prognosis and treatment. Airway macrophages are important innate immune cells with roles in both the induction and resolution of tissue inflammation.ObjectivesTo investigate airway innate immune cellular phenotypes in preterm infants with respiratory distress syndrome (RDS) or CLD.MethodsBronchoalveolar lavage (BAL) fluid was obtained from term and preterm infants requiring mechanical ventilation. BAL cells were phenotyped by flow cytometry.ResultsPreterm birth was associated with an increase in the proportion of non-classical CD14+/CD16+ monocytes on the day of delivery (58.9±5.8% of total mononuclear cells in preterm vs 33.0±6.1% in term infants, p = 0.02). Infants with RDS were born with significantly more CD36+ macrophages compared with the CLD group (70.3±5.3% in RDS vs 37.6±8.9% in control, p = 0.02). At day 3, infants born at a low gestational age are more likely to have greater numbers of CD14+ mononuclear phagocytes in the airway (p = 0.03), but fewer of these cells are functionally polarized as assessed by HLA-DR (p = 0.05) or CD36 (p = 0.05) positivity, suggesting increased recruitment of monocytes or a failure to mature these cells in the lung.ConclusionsThese findings suggest that macrophage polarization may be affected by gestational maturity, that more immature macrophage phenotypes may be associated with the progression of RDS to CLD and that phenotyping mononuclear cells in BAL could predict disease outcome.
    PLoS ONE 08/2014; 9(8):e103059. DOI:10.1371/journal.pone.0103059 · 3.23 Impact Factor
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    • "Also of concern is the potential for immune tolerance as routinely demonstrated in models of oral vaccination (Fattal et al. 2002; Gupta et al. 2007; Adam and Wright 2009). Nanotechnology is emerging as a feasible approach to target activation of immune responses and promises to be an effective strategy to overcome current limitations mentioned above (Marriott et al. 2006; Gupta et al. 2007). We are particularly interested in the use of PLGA NPs. "
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    ABSTRACT: Nanoparticle (NP) technologies are becoming commonplace in the development of vaccine delivery systems to protect against various diseases. The current study determined the efficacy of intranasal delivery of a 234 ± 87.5 nm poly lactic-co-glycolic acid nanoparticle vaccine construct in establishing protection against experimental respiratory pneumococcal infection. Nanoparticles encapsulating heat-killed Streptococcus pneumoniae (NP-HKSP) were retained in the lungs 11 days following nasal administration compared to empty NP. Immunization with NP-HKSP produced significant resistance against S. pneumoniae infection compared to administration of HKSP alone. Increased protection correlated with a significant increase in antigen-specific Th1-associated IFN-γ cytokine response by pulmonary lymphocytes. This study establishes the efficacy of NP-based technology as a non-invasive and targeted approach for nasal-pulmonary immunization against pulmonary infections.
    Journal of Nanoparticle Research 05/2013; 15(5):1-7. DOI:10.1007/s11051-013-1646-x · 2.18 Impact Factor
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    • "Alveolar macrophages, as sentinel cells, play a critical role through both cell-intrinsic antimicrobial functions (e.g., generation of oxidants) and production of cytokines that recruit microbicidal neutrophils (PMNs) into the infected airspace. Ultimately, death of macrophages and PMNs through apoptosis is coupled to their production of oxidants and is critical for successful bacterial clearance (Marriott et al., 2006). Given the importance of these various cellular functions to host defense, we speculated that the ubiquitously expressed tumor suppressor p53 might be positioned to regulate multiple critical checkpoints in the host defense response to extracellular pathogens in vivo. "
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    ABSTRACT: Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53(-/-) mice display genome-wide induction of NF-κB response element-enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor-treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53(-/-) neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53(-/-) mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult.
    Journal of Experimental Medicine 04/2013; 210(5). DOI:10.1084/jem.20121674 · 12.52 Impact Factor
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