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

Abstract

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.

Allergic Lung Inflammation Reduces Tissue Invasion and Enhances Survival from Pulmonary Pneumococcal Infection in Mice, Which Correlates with Increased Expression of Transforming Growth Factor β1 and SiglecF low Alveolar Macrophages

“…We concluded from these results that eosinophils and neutrophils were not required for enhanced resistance to pneumococcal pneumonia following ALI. In contrast to our findings, increased resistance of mice to Klebsiella pneumoniae following ALI did require neutrophils (32), a finding that is consistent with a requirement of neutrophils for protection against pulmonary K. pneumoniae infections (35). For pneumococcal infection, on the other hand, neutrophil recruitment is thought to play a major role in control of bacterial colonization while having a limited impact during acute lung infections (36)(37)(38).…”

Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury

“…Mice were anesthetized with ketamine and xylazine and 2 × 10 3 colony forming units were administered intra-nasally32. Samples were collected after 6, 24, 48, or 72 hours.…”

Allergic Asthma Favors Brucella Growth in the Lungs of Infected Mice

“…This suggests that strong neutrophilia induced by asthma sensitization in STAT-6 −/− mice (Figure S2 in Supplementary Material) could be sufficient to increase resistance to S. pneumoniae in our model. Interestingly, a recent study ( 79 ) in a mouse model reported that allergic asthma also decreases lung infection with Klebsiella pneumoniae in a neutrophil-dependent and IL-4- and IL-17-independent manner.…”