Inescapable Need for Neutrophils as Mediators of Cellular Innate Immunity to Acute Pseudomonas aeruginosa Pneumonia

Abstract

Pseudomonas aeruginosa is a leading cause of pneumonia, and many components of the innate immune system have been proposed to exert important effects in preventing lung infection. However, a vigorous experimental system to identify an overriding, key effector mediating innate immunity to lung infection has not been utilized. As many of the important components of innate immunity are involved in recruitment and activation of polymorphonuclear neutrophils (PMNs) to infected tissues, we hypothesized that the cells and factors needed for their proper recruitment to the lung comprised the major mediators of innate immunity. In neutropenic mice, intranasal (i.n.) doses of P. aeruginosa as low as 10 to 100 CFU/mouse produced a fatal lung infection, compared with 10 7 to >10 8 CFU for nonneutropenic mice. There was only a very modest increased mortality in mice lacking mature lymphocytes and no increased mortality in mice depleted of alveolar macrophages when administered i.n. P. aeruginosa. Recombinant mouse granulocyte colony-stimulating factor increased survival of neutropenic mice after i.n. P. aeruginosa inoculation. MyD88 ؊/؊ mice, which cannot recruit PMNs to the lungs, were highly susceptible to fatal P. aeruginosa lung infection, with bacterial doses of <120 CFU being lethal. Activation of a MyD88-independent pathway for PMN recruitment to the lungs in MyD88 ؊/؊ mice resulted in enhanced protection against P. aeruginosa lung infection. Overall, in the absence of PMNs, mice cannot resist P. aeruginosa lung infection from extremely small bacterial doses. There is an inescapable requirement for local PMN recruitment and activation to mediate innate immunity to P. aeruginosa lung infection.

Alterations in Ceramide Concentration and pH Determine the Release of Reactive Oxygen Species by Cftr-Deficient Macrophages on Infection

“…Although several studies have demonstrated that Cftr-deficient macrophages exhibit a defect in the intracellular killing of P. aeruginosa (4, 7), the role of macrophages in acute pulmonary infections with P. aeruginosa in vivo is still open (33). A recent study demonstrated that in particular neutrophils are essential in eliminating P. aeruginosa from infected airways (33).…”

Activated β2 Integrins Restrict Neutrophil Recruitment during Murine Acute Pseudomonal Pneumonia

“…Neutrophils are essential for host defense against P. aeruginosa and other bacterial infections of the lungs (32,(36)(37)(38). Neutropenic human patients (39,40) and laboratory mice (36,41,42) have enhanced susceptibility to pseudomonal pneumonia.…”

“…Neutropenic human patients (39,40) and laboratory mice (36,41,42) have enhanced susceptibility to pseudomonal pneumonia. Inefficient rapid, early neutrophil recruitment, even when corrected within 24 hours, resulted in 10-fold more bacteria in the airspaces at 48 hours in a murine model of pneumococcal pneumonia (43).…”

Modulation of Dendritic Cell Differentiation in the Bone Marrow Mediates Sustained Immunosuppression after Polymicrobial Sepsis

“…Previous experiments have shown that the bacterial load in the lungs of naive mice postinfection with P. aeruginosa was independent from simultaneously applied Sham-BMDC (data not shown), indicating that Sham-BMDC do not improve the clearance of bacteria through mechanisms that might lack in CLP-BMDC. Granulocytes and NK cells are required for an effective defense against P. aeruginosa infection in the lung (23,24) and, thus, might be target cells of the CLP-BMDC-mediated suppression of the immune response against P. aeruginosa. However, the finding that CLP-BMDC did not significantly alter the number or the maturation state of recruited granulocytes in the lung (Fig.…”