The lungs are not sterile or free from bacteria; rather, they harbor a distinct microbiome whose composition is driven by different ecological rules than for the gastrointestinal tract. During ...disease, there is often a shift in community composition towards Gammaproteobacteria, the bacterial class that contains many common lung-associated gram-negative "pathogens." Numerous byproducts of host inflammation are growth factors for these bacteria. The extracellular nutrient supply for bacteria in the lungs, which is severely limited during health, markedly increases due to the presence of mucus and vascular permeability. While Gammaproteobacteria benefit from airway inflammation, they also encode molecular components that promote inflammation, potentially creating a cyclical inflammatory mechanism. In contrast, Prevotella species that are routinely acquired via microaspiration from the oral cavity may participate in immunologic homeostasis of the airways.vAreas of future research include determining for specific lung diseases (1) whether an altered lung microbiome initiates disease pathogenesis, promotes chronic inflammation, or is merely a marker of injury and inflammation, (2) whether the lung microbiome can be manipulated therapeutically to change disease progression, (3) what molecules (metabolites) generated during an inflammatory response promote cross-kingdom signaling, and (4) how the lung "ecosystem" collapses during pneumonia, to be dominated by a single pathogen.
Regulation of respiratory mucosal immunity by microbial-derived metabolites has been a proposed mechanism that may provide airway protection. Here we examine the effect of oral Lactobacillus ...johnsonii supplementation on metabolic and immune response dynamics during respiratory syncytial virus (RSV) infection. L. johnsonii supplementation reduced airway T helper type 2 cytokines and dendritic cell (DC) function, increased regulatory T cells, and was associated with a reprogrammed circulating metabolic environment, including docosahexanoic acid (DHA) enrichment. RSV-infected bone marrow-derived DCs (BMDCs) from L. johnsonii-supplemented mice had altered cytokine secretion, reduced expression of co-stimulatory molecules, and modified CD4+ T-cell cytokines. This was replicated upon co-incubation of wild-type BMDCs with either plasma from L. johnsonii-supplemented mice or DHA. Finally, airway transfer of BMDCs from L. johnsonii-supplemented mice or with wild-type derived BMDCs pretreated with plasma from L. johnsonii-supplemented mice reduced airway pathological responses to infection in recipient animals. Thus L. johnsonii supplementation mediates airway mucosal protection via immunomodulatory metabolites and altered immune function.
Specific components of the intestinal microbiota are capable of influencing immune responses such that a mutualistic relationship is established. In mice, colonization with segmented filamentous ...bacteria (SFB) induces T-helper-17 (Th17) cell differentiation in the intestine, yet the effector functions of interleukin (IL)-17A in response to SFB remain incompletely understood. Here we report that colonization of mice with SFB-containing microbiota induced IL-17A- and CXCR2-dependent recruitment of neutrophils to the ileum. This response required adaptive immunity, as Rag-deficient mice colonized with SFB-containing microbiota failed to induce IL-17A, CXCL1 and CXCL2, and displayed defective neutrophil recruitment to the ileum. Interestingly, neutrophil depletion in wild-type mice resulted in significantly augmented Th17 responses and SFB expansion, which correlated with impaired expression of IL-22 and antimicrobial peptides. These data provide novel insight into a dynamic IL-17A-CXCR2-neutrophil axis during acute SFB colonization and demonstrate a central role for neutrophils in limiting SFB expansion.
The prevalence of asthma has risen drastically in the last two decades, with a worldwide impact on health care systems. Although several factors contribute to the development of asthma, inflammation ...seems to be a common factor that leads to the most severe asthmatic responses. In the past decade, researchers have characterized a large group of chemotactic cytokines, also known as chemokines, which are implicated in asthmatic inflammation. These chemokines control and direct the migration and activation of various leukocyte populations. Targeting chemokines should lead to new ways of controlling the inflammatory asthmatic response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
While recent studies suggest that interleukin (IL)-1β production is modulated by macroautophagy or sensors of endoplasmic reticulum (ER) stress upon pro-inflammatory insult, autophagy and IL-1β ...production during viral infection has not been fully investigated. This was addressed using respiratory syncytial virus (RSV), which is associated with lung immunopathology, IL-1, and IL-17a secretion in severely infected patients. Mice deficient in the autophagy-associated protein Map1-LC3b (LC3b(-/-)) developed increased IL-17a-dependent lung pathology upon infection. RSV-infected LC3b(-/-) dendritic cells (DCs) fail to upregulate autophagosome formation, secrete IL-1β and IL-6, and elicit IL-17a production from CD4+ T cells. Bone marrow chimeras revealed that both structural and hematopoietic LC3b deficiency contribute to the development of IL-17a-dependent lung pathology in vivo. Further investigation revealed airway epithelium as the primary source of IL-1β during infection, whereas inhibition of the ER-stress sensor inositol-requiring protein-1 in primary airway epithelial cells reduced IL-1β production identifying a primary ER stress pathway. Finally, blockade of IL-1 receptor signaling in RSV-infected LC3b(-/-) mice abolished IL-17a-dependent lung pathology. These findings provide novel mechanistic insight into the contribution of autophagy- and ER stress-dependent cytokine production that initiate and maintain aberrant Th17 responses, while identifying IL-1 as a potential therapeutic target in the treatment of severe respiratory viral infections.
Respiratory syncytial virus (RSV) is a negative-sense, single-strand RNA virus that can initiate severe bronchiolitis in infants, as well as in elderly adults. Although RSV preferentially infects and ...replicates in the airway epithelium, studies have shown that RSV has the ability to infect and, to a limited extent, replicate in alveolar macrophages. In the present study, we sought to characterize the RSV-induced chemokine production in vitro and in vivo, because chemokines have been shown to contribute to both the inflammation and pathophysiology of disease. Our results show that RSV-infected airway epithelial cells and alveolar macrophages display differential profiles of chemokine production: airway epithelial cells produce CCL2/monocyte chemoattractant protein-1, CCL5/RANTES, CXCL10/gamma interferon inducible protein-10, and kerotinocyte cytokine (KC); and alveolar macrophages up-regulate CCL5 and macrophage inflammatory protein (MIP)-2 after RSV infection. In vivo, we observed the induction of CCL2, CCL3/MIP-1α, CCL5, CXCL10, and KC after RSV infection. In the present study, we also addressed the necessity for viral infection and/or replication in chemokine induction by use of ultraviolet (UV)-inactivated RSV, as well as RSV inhibitors of binding/infection and replication, that is, NMSO3, a sulfated sialyl lipid compound, and ribavirin, respectively. Our results suggest that viral replication is necessary for optimal chemokine production.
Leptin is an adipocyte-derived hormone that is secreted in correlation with total body lipid stores. Serum leptin levels are lowered by the loss of body fat mass that would accompany starvation and ...malnutrition. Recently, leptin has been shown to modulate innate immune responses such as macrophage phagocytosis and cytokine synthesis in vitro. To determine whether leptin plays a role in the innate host response against Gram-negative pneumonia in vivo, we compared the responses of leptin-deficient and wild-type mice following an intratracheal challenge of Klebsiella pneumoniae. Following K. pneumoniae administration, we observed increased leptin levels in serum, bronchoalveolar lavage fluid, and whole lung homogenates. In a survival study, leptin-deficient mice, as compared with wild-type mice, exhibited increased mortality following K. pneumoniae administration. The increased susceptibility to K. pneumoniae in the leptin-deficient mice was associated with reduced bacterial clearance and defective alveolar macrophage phagocytosis in vitro. The exogenous addition of very high levels of leptin (500 ng/ml) restored the defect in alveolar macrophage phagocytosis of K. pneumoniae in vitro. While there were no differences between wild-type and leptin-deficient mice in lung homogenate cytokines TNF-alpha, IL-12, or macrophage-inflammatory protein-2 after K. pneumoniae administration, leukotriene synthesis in lung macrophages from leptin-deficient mice was reduced. Leukotriene production was restored by the addition of exogenous leptin (500 ng/ml) to macrophages in vitro. This study demonstrates for the first time that leptin-deficient mice display impaired host defense in bacterial pneumonia that may be due to a defect in alveolar macrophage phagocytosis and leukotriene synthesis.
The generation of regulatory T (Treg) cells is driven by Foxp3 and is responsible for dampening inflammation and reducing autoimmunity. In this study, the epigenetic regulation of inducible Treg ...(iTreg) cells was examined and an H3K4 histone methyltransferase, SMYD3 (SET and MYND Domain 3), which regulates the expression of Foxp3 by a TGFβ1/Smad3 (transforming growth factor-β1/Smad3)-dependent mechanism, was identified. Using chromatin immunoprecipitation assays, SMYD3 depletion led to a reduction in H3K4me3 in the promoter region and CNS1 (conserved noncoding DNA sequence) of the foxp3 locus. SMYD3 abrogation affected iTreg cell formation while allowing dysregulated interleukin-17 production. In a mouse model of respiratory syncytial virus (RSV) infection, a model in which iTreg cells have a critical role in regulating lung pathogenesis, SMYD3(-/-) mice demonstrated exacerbation of RSV-induced disease related to enhanced proinflammatory responses and worsened pathogenesis within the lung. Our data highlight a novel activation role for the TGFβ-inducible SMYD3 in regulating iTreg cell formation leading to increased severity of virus-related disease.
Hematopoietic stem cell transplantation (HSCT) efficacy is limited by numerous pulmonary complications. We developed a model of syngeneic bone marrow transplantion (BMT) followed by infection with ...murine gamma herpesvirus-68 that results in pneumonitis and fibrosis and mimics human "noninfectious" HSCT complications. BMT mice experience increased early lytic replication, but establish viral latency by 21 days post infection. CD4 T cells in BMT mice are skewed toward interleukin (IL)-17A rather than interferon (IFN)-γ production. Transplantation of bone marrow from Il-17a(-/-) donors or treatment with anti-IL-17A neutralization antibodies at late stages attenuates pneumonitis and fibrosis in infected BMT mice, suggesting that hematopoietic-derived IL-17A is essential for development of pathology. IL-17A directly influences activation and extracellular matrix production by lung mesenchymal cells. Lung CD11c+ cells of BMT mice secrete more transforming growth factor beta-β1, and pro-TH17 mRNAs for IL-23 and IL-6, and less TH1-promoting cytokine mRNA for IFN-γ but slightly more IL-12 mRNA in response to viral infection. Adoptive transfer of non-BMT lung CD11c-enriched cells restores robust TH1 response and suppresses aberrant TH17 response in BMT mice to improve lung pathology. Our data suggest that "noninfectious" HSCT lung complications may reflect preceding viral infections and demonstrate that IL-17A neutralization may offer therapeutic advantage even after disease onset.
Monocyte chemoattractant protein 1 (MCP-1) is a CC chemokine that attracts monocytes, memory T lymphocytes, and natural killer cells. Because other chemokines have similar target cell specificities ...and because CCR2, a cloned MCP-1 receptor, binds other ligands, it has been uncertain whether MCP-1 plays a unique role in recruiting mononuclear cells in vivo. To address this question, we disrupted SCYA2 (the gene encoding MCP-1) and tested MCP-1-deficient mice in models of inflammation. Despite normal numbers of circulating leukocytes and resident macrophages, MCP-1(-/-) mice were specifically unable to recruit monocytes 72 h after intraperitoneal thioglycollate administration. Similarly, accumulation of F4/80+ monocytes in delayed-type hypersensitivity lesions was impaired, although the swelling response was normal. Development of secondary pulmonary granulomata in response to Schistosoma mansoni eggs was blunted in MCP-1(-/-) mice, as was expression of IL-4, IL-5, and interferon gamma in splenocytes. In contrast, MCP-1(-/-) mice were indistinguishable from wild-type mice in their ability to clear Mycobacterium tuberculosis. Our data indicate that MCP-1 is uniquely essential for monocyte recruitment in several inflammatory models in vivo and influences expression of cytokines related to T helper responses.
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