Importance of CXC chemokine receptor 2 in alveolar neutrophil and exudate macrophage recruitment in response to pneumococcal lung infection.

Sustained neutrophilic infiltration is known to contribute to organ damage, such as acute lung injury. CXC chemokine receptor 2 (CXCR2) is the major receptor regulating inflammatory neutrophil recruitment in acute and chronic inflamed tissues. Whether or not the abundant neutrophil recruitment observed in severe pneumonia is essential for protective immunity against Streptococcus pneumoniae infections is incompletely defined. Here we show that CXCR2 deficiency severely perturbs the recruitment of both neutrophils and exudate macrophages associated with a massive bacterial outgrowth in distal airspaces after infection with S. pneumoniae, resulting in 100% mortality in knockout (KO) mice within 3 days. Moreover, irradiated wild-type mice reconstituted with increasing amounts of CXCR2 KO bone marrow (10, 25, 50, and 75% KO) have correspondingly decreased numbers of both neutrophils and exudate macrophages, which is associated with a stepwise increase in bacterial burden and a reciprocal stepwise decrease in survival in S. pneumoniae-induced pulmonary infection. Finally, application of the CXCR2 antagonist SB-225002 resulted in decreased alveolar neutrophil and exudate macrophage recruitment in mice along with increased lung bacterial loads after infection with S. pneumoniae. Together, these data show that CXC chemokine receptor 2 serves a previously unrecognized nonredundant role in the regulation of both neutrophil and exudate macrophage recruitment to the lung in response to S. pneumoniae infection. In addition, we demonstrate that a threshold level of 10 to 25% of reduced neutrophil recruitment is sufficient to cause increased mortality in mice infected with S. pneumoniae.

Important role for CC chemokine ligand 2-dependent lung mononuclear phagocyte recruitment to inhibit sepsis in mice infected with Streptococcus pneumoniae.

The monocyte chemoattractant CCL2 is of major importance in inflammatory monocyte recruitment to the lungs in response to bacterial infection. Streptococcus pneumoniae is the most prevalent pathogen in community-acquired pneumonia causing significant morbidity and mortality worldwide. In the current study, we examined the role of CCL2 in lung-protective immunity against two strains of S. pneumoniae exhibiting different virulence profiles. Both wild-type mice and CCL2 knockout (KO) mice became septic within 24 h of infection with serotype 3 S. pneumoniae and died of infection by day 4 after challenge. In contrast, wild-type mice challenged with serotype 19 S. pneumoniae did not become septic or succumb to pneumococcal pneumonia, whereas CCL2 KO mice showed an early bacterial outgrowth in their lungs and sepsis starting by day 2 after infection, finally resulting in approximately 50% decreased survival compared with wild-type mice. This phenotype was not due to impaired lung neutrophil recruitment in the KO mice, but was characterized by a significantly reduced recruitment of lung exudate macrophages and conventional lung dendritic cells, suggesting that these two phagocyte subsets critically regulate protection against septic disease progression in mice. In conclusion, we show here a differential role for CCL2-dependent lung exudate macrophage and conventional dendritic cell recruitment that critically contributes to lung protective immunity against S. pneumoniae.