Important Role for CC Chemokine Ligand 2-Dependent Lung Mononuclear Phagocyte Recruitment to Inhibit Sepsis in Mice Infected with Streptococcus pneumoniae

Abstract

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 ∼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.

Chemokine Receptor 2-Mediated Accumulation of Fungicidal Exudate Macrophages in Mice That Clear Cryptococcal Lung Infection

“…45 Our gating strategy distinguishes ExMs from AMs, which are both CD11c ϩ AF ϩ on the basis of CD11b expression (present on ExMs and absent on AMs), as recently described. [33][34][35][36] In those studies, ExMs were specifically identified in the lungs of mice with bacterial or viral pneumonia, in which the numbers were much smaller than in the current study. The impressive quantity of ExMs that we identify in this model likely reflects the substantial inflammation induced by cryptococcal lung infection, with recruitment of up to 100 million CD45 ϩ leukocytes per mouse and critical reliance on lung macrophages for clearance of this organism.…”

“…33,34 In contrast, ExMs express little MHC class II or CD86 in the lungs of mice infected with Streptococcus pneumoniae, an extracellular bacterial pathogen cleared primarily by innate mechanisms. 35 We further show that expression of macrophage-associated proteins and costimulatory molecules is not uniform but varies at different times after infection. Collectively, these data imply that the ExM phenotype may vary according to the following: i) the class of infecting pathogen, ii) whether innate or adaptive immune mechanisms are required for microbial clearance, and iii) the inflammatory milieu within the pulmonary microenvironment during different phases of infection.…”

“…Next, we set consecutive gates which identified CD11c ϩ cells ( Figure 1A, left dot plot) and distinguished autofluorescent (AF ϩ ) macrophages from non-AF (AF Ϫ ) dendritic cells (DCs) ( Figure 1A, middle dot plot), as previously described. 41,45,[51][52][53] Last, we used relative expression of CD11b to distinguish CD11b-negative AMs (CD11c ϩ AF ϩ CD11b Ϫ ) 42,54,55 and CD11b-positive ExMs (CD11c ϩ AF ϩ CD11b ϩ ) 33,35 ( Figure 1A, right dot plot; gates labeled AM and ExM). Proper gate placement for AF and expression of CD11c and CD11b were determined using AMs obtained from bronchoalveolar lavage fluid of uninfected mice (which consists of Ͼ90% CD11c ϩ AF ϩ CD11b Ϫ AMs; data not shown).…”

“…[33][34][35][36] Expression of CD11b, along with varying reports of increased major histocompatibility complex (MHC) class II and costimulatory molecules, distinguishes ExMs from AMs. 33 Exudate macrophages express iNOS indicative of effector function.…”

Distinct Macrophage Subpopulations Characterize Acute Infection and Chronic Inflammatory Lung Disease

“…Cell turnover rate is slow (11) and is maintained by constitutively immigrating CCR2 2 Gr-1 2 resident monocytes (12,13). In contrast, CCR2 + Gr-1 + inflammatory monocytes rapidly migrate into alveolar airspaces after lung infection and are believed to be the main effectors of acute lung injury and infection-related mortality (6,14,15). Increased AMFs, however, are correlated with the severity of chronic obstructive pulmonary disease (COPD) (16), a debilitating chronic condition characterized by progressive irreversible airflow limitation and lung parenchyma destruction.…”