The Journal of immunology : official journal of the American Association of Immunologists
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Sepsis commonly results in acute and chronic brain dysfunction, which dramatically increases the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. However, we have found previously that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. ⋯ S100A9 expression is necessary for recruitment of neutrophils to the brain and for priming production of reactive oxygen species and TNF-α secretion in microglia and macrophages. However, despite improving these indices of chronic inflammation, S100A9 deficiency results in worsened anxiety-like behavior 2 wk after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial-reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors.
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Indirect acute respiratory distress syndrome (iARDS) is caused by a nonpulmonary inflammatory process resulting from insults such as nonpulmonary sepsis. Neutrophils are thought to play a significant role in mediating ARDS, with the development of iARDS being characterized by dysregulation and recruitment of activated neutrophils into the lung. Recently, a novel mechanism of microbial killing by neutrophils was identified through the formation of neutrophil extracellular traps (NETs). ⋯ PAD4-/- mice displayed a marked decrease in neutrophil influx into the lung, as well decreased presence of proinflammatory mediators. PAD4-/- mice were also able to maintain baseline kidney function after Hem/CLP. These data taken together suggest PAD4-mediated NET formation contributes to the mortality associated with shock/sepsis and may play a role in the pathobiology of end organ injury in response to combined hemorrhage plus sepsis.
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Respiratory syncytial virus (RSV) infection induces asthma exacerbations, which leads to worsening of clinical symptoms and may result in a sustained decline in lung function. Exacerbations are the main cause of morbidity and mortality associated with asthma, and significantly contribute to asthma-associated healthcare costs. Although glucocorticoids are used to manage exacerbations, some patients respond to them poorly. ⋯ Stimulation of pulmonary macrophages with TNF-α and/or MCP-1 induced expression of both IFN-γ and IL-27. Our findings highlight critical roles for IFN-γ and IL-27, downstream of TNF-α and MCP-1, in the mechanism of RSV-induced exacerbation. Thus, targeting the pathways that these factors activate may be a potential therapeutic approach for virus-induced asthma exacerbations.
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Orosomucoid like 3 (ORMDL3), a gene localized to chromosome 17q21, has been linked in epidemiologic studies to childhood asthma and rhinovirus (RV) infections. As the single nucleotide polymorphisms linking ORMDL3 to asthma are associated with increased expression of ORMDL3, we have used hORMDL3zp3-Cre mice (which have universal increased expression of human ORMDL3) to determine whether infection of these transgenic mice with RV influences levels of airway inflammation or RV viral load. RV infection of hORMDL3zp3-Cre mice resulted in reduced RV viral load assessed by quantitative real-time PCR (lung and airway epithelium), as well as reduced airway inflammation (total bronchoalveolar lavage cells, neutrophils, macrophages, and lymphocytes) compared with RV-infected wild-type mice. ⋯ In addition, levels of mOas2, but not mOas1 (mOas1a, mOas1b, mOas1g), or mOas3 pathways were significantly more upregulated by IFNs (IFN-α, IFN-β, IFN-λ) in epithelial cells from hORMDL3zp3-Cre mice compared with RV-infected wild-type mouse epithelial cells. RNAse L-deficient mice infected with RV had increased RV viral load. Overall, these studies suggest that increased levels of ORMDL3 contribute to antiviral defense to RV infection in mice through pathways that may include IFNs (IFN-α, IFN-β, IFN-λ), OAS, and RNAse L.
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Robust lung inflammation is one of the prominent features in the pathogenesis of acute lung injury (ALI). Macrophage migration and recruitment are often seen at the early stage of lung inflammatory responses to noxious stimuli. Using an acid inhalation-induced lung injury model, we explored the mechanisms by which acid exposure initiates macrophage recruitment and migration during development of ALI. ⋯ Mechanistically, acid-induced epithelial MV miR-17/221 promoted β1 integrin recycling and presentation back onto the surface of macrophages, in part via a Rab11-mediated pathway. Integrin β1 is known to play an essential role in regulating macrophage migration. Taken together, acid-induced ALI results in epithelial MV shuttling of miR-17/221 that in turn modulates macrophage β1 integrin recycling, promoting macrophage recruitment and ultimately contributing to lung inflammation.