Mast Cell IL-6 Improves Survival from <i>Klebsiella</i> Pneumonia and Sepsis by Enhancing Neutrophil Killing

Sutherland, Robert M.; Olsen, Joanna S.; McKinstry, Andrew; Villalta, S. Armando; Wolters, Paul J.

doi:10.4049/jimmunol.181.8.5598

Cited by 139 publications

(135 citation statements)

References 55 publications

(51 reference statements)

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“…We next investigated the influence of allergic airway inflammation on acute-phase cytokine and chemokine expression in the lung following K. pneumoniae infection. Numerous cytokines and chemokines have been implicated in the protective response to lung K. pneumoniae infection (6,19,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). At both day 1 and day 2 following infection, ALUM-KP mice had significantly increased lung expression of acute-phase cytokines (TNF-␣, IL-6, IL-1␤), chemokines (CXCL1, CCL3, CCL4), G-CSF, and GM-CSF compared to both ALUM-PBS and OVA-PBS mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

et al. 2014

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f The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.

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Section: Resultsmentioning

confidence: 99%

Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

et al. 2014

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“…Surprisingly, IL-6 overexpression even protected mice against hyperoxic lung injury by regulating Bax and reducing apoptosis through a PI-3 kinase pathway (22). In turn, IL-6 generated by mast cells improved survival during sepsis by enhancing neutrophil killing of bacteria (32) and reduced DNA damage during hypoxia (37). IL-6 from a hematopoietic cell source limited alveolar barrier disruption potentially by reducing neutrophil contact with the endothelium (38).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Rho signaling by pathologic mechanical stretch is a “second hit” to Rho-independent lung injury induced by IL-6

Birukova

Tian

Meliton

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Birukova AA, Tian Y, Meliton A, Leff A, Wu T, Birukov KG. Stimulation of Rho signaling by pathologic mechanical stretch is a "second hit" to Rho-independent lung injury induced by IL-6. Am J Physiol Lung Cell Mol Physiol 302: L965-L975, 2012. First published February 17, 2012 doi:10.1152/ajplung.00292.2011.-Most patients with acute lung injury (ALI) and acute respiratory distress syndrome of septic and nonseptic nature require assisted ventilation with positive pressure, which at suboptimal range may further exacerbate lung dysfunction. Previous studies described enhancement of agonist-induced Rho GTPase signaling and endothelial cell (EC) permeability in EC cultures exposed to pathologically relevant cyclic stretch (CS) magnitudes. This study examined a role of pathologic CS in modulation of pulmonary EC permeability caused by IL-6, a cytokine increased in sepsis and acting in a Rho-independent manner. IL-6 increased EC permeability, which was associated with activation of Jak/signal transducers and activators of transcription, p38 MAP kinase, and NF-B signaling and was augmented by EC exposure to 18% CS. Rho kinase inhibitor Y-27632 suppressed the synergistic effect of 18% CS on IL-6-induced EC monolayer disruption but did not alter the IL-6 effects on static EC culture. 18% CS also increased IL-6-induced ICAM-1 expression by pulmonary EC and neutrophil adhesion, which was attenuated by Y-27632. Intratracheal IL-6 administration in C57BL/6J mice increased protein content and cell count in bronchoalveolar lavage fluid. These changes were augmented by high tidal volume mechanical ventilation (HTV; 30 ml/kg, 4 h). Intravenous injection of Y-27632 suppressed IL6/HTV-induced lung injury. In conclusion, this study proposes a novel mechanism contributing to two-hit model of ALI: in addition to synergistic effects on Rho-dependent endothelial hyper-permeability triggered by thrombin, TNF␣, LPS, or other agonists, ventilator-induced lung injury-relevant CS may also exacerbate Rho-independent mechanisms of EC permeability induced by other inflammatory mediators such as IL-6 via mechanisms involving Rho activity. cyclic stretch; actin; interleukin-6; vascular permeability; endothelium VENTILATOR SUPPORT IS AN INDISPENSABLE treatment for critically ill patients. However, suboptimal regimen of mechanical ventilation leading to ventilator-induced lung injury (VILI), multiorgan dysfunction, and high rates of morbidity and mortality remain one of the most important problems in the management of patients with preexisting respiratory complications in the intensive care unit (31, 34).Pathologic mechanical forces leading to VILI trigger several signaling mechanisms including activation of signaling kinases, ion channels, small GTPases, second messengers, inflammatory signaling, and gene expression (14,16,39). Increased vascular endothelial permeability (2), inflammatory cytokine production (41), and apoptosis (18) induced by pathological mechanical stimulation causes alveolar flooding, leukocyte infiltration, and hypoxemia leadi...

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“…Indeed, there is evidence that several mast cell products can enhance survival during innate immune responses to bacterial infection. In studies of moderately severe CLP, it has been reported that mast cells can enhance survival by production of interleukin-6 42 or by the action of mast cell-associated proteases including mast cell carboxypeptidase A or neurolysin (which can enhance survival by degrading potentially toxic endogenous peptides produced during CLP, such as endothelin-1 8,13 or neurolysin 13 ). In studies of mice injected intraperitoneally with K. pneumoniae, survival can be enhanced by mouse mast cell protease 6.…”

Section: Discussionmentioning

confidence: 99%

Mast Cell-Derived TNF Can Exacerbate Mortality during Severe Bacterial Infections in C57BL/6-Kit Mice

Piliponsky

Chen

Grimbaldeston

et al. 2010

The American Journal of Pathology

129

174

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We used mast cell-engrafted genetically mast cell-deficient C57BL/6-Kit W-sh/W-sh mice to investigate the roles of mast cells and mast cell-derived tumor necrosis factor in two models of severe bacterial infection. In these mice, we confirmed findings derived from studies of mast cell-deficient WBB6F 1 -Kit W/W-v mice indicating that mast cells can promote survival in cecal ligation and puncture (CLP) of moderate severity. However, we found that the beneficial role of mast cells in this setting can occur independently of mast cell-derived tumor necrosis factor. By contrast, using mast cell-engrafted C57BL/6-Kit W-sh/W-sh mice, we found that mast cell-derived tumor necrosis factor can increase mortality during severe CLP and can also enhance bacterial growth and hasten death after intraperitoneal inoculation of Salmonella typhimurium. In WBB6F 1 -Kit W-sh/W-sh mice, mast cells enhanced survival during moderately severe CLP but did not significantly change the survival observed in severe CLP. Our findings in three types of genetically mast celldeficient mice thus support the hypothesis that, depending on the circumstances (including mouse strain background, the nature of the mutation resulting in a mast cell deficiency, and type and severity of infection), mast cells can have either no detectable effect or opposite effects on survival during bacterial infections, eg, promoting survival during moderately severe CLP associated with low mortality but, in C57BL/ 6-Kit W-sh/W-sh mice, increasing mortality during severe CLP or infection with S. typhimurium. (Am J Pathol

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Mast Cell IL-6 Improves Survival from Klebsiella Pneumonia and Sepsis by Enhancing Neutrophil Killing

Cited by 139 publications

References 55 publications

Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

Stimulation of Rho signaling by pathologic mechanical stretch is a “second hit” to Rho-independent lung injury induced by IL-6

Mast Cell-Derived TNF Can Exacerbate Mortality during Severe Bacterial Infections in C57BL/6-Kit Mice

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