Heterogeneity of lung mononuclear phagocytes during pneumonia: contribution of chemokine receptors

Abstract

Bacterial pneumonia is a common and dangerous illness. Mononuclear phagocytes, which comprise monocyte, resident and recruited macrophage, and dendritic cell subsets, are critical to antimicrobial defenses, but the dynamics of their recruitment to the lungs in pneumonia is not established. We hypothesized that chemokine-mediated traffic of mononuclear phagocytes is important in defense against bacterial pneumonia. In a mouse model of Klebsiella pneumonia, circulating Ly6Chi and, to a lesser extent, Ly6Clo monocytes expanded in parallel with accumulation of inflammatory macrophages and CD11bhi dendritic cells and plasmacytoid dendritic cells in the lungs, whereas numbers of alveolar macrophages remained constant. CCR2 was expressed by Ly6Chi monocytes, recruited macrophages, and airway dendritic cells; CCR6 was prominently expressed by airway dendritic cells; and CX3CR1 was ubiquitously expressed by blood monocytes and lung CD11bhi dendritic cells during infection. CCR2-deficient, but not CCL2-, CX3CR1-, or CCR6-deficient animals exhibited worse outcomes of infection. The absence of CCR2 had no detectable effect on neutrophils but resulted in reduction of all subsets of lung mononuclear phagocytes in the lungs, including alveolar macrophages and airway and plasmacytoid dendritic cells. In addition, absence of CCR2 skewed the phenotype of lung mononuclear phagocytes, abrogating the appearance of M1 macrophages and TNF-producing dendritic cells in the lungs. Taken together, these data define the dynamics of mononuclear phagocytes during pneumonia.

Ly6Chigh Monocytes Protect against Kidney Damage during Sepsis via a CX3CR1-Dependent Adhesion Mechanism

“…Previous studies have shown that inflammatory monocytes are involved in controlling inflammation in gram-negative pneumonia and abdominal infections. 8,9,[38][39][40][41][42] A lower number of inflammatory monocytes has been associated with increased lesions in the lung and in the intestinal lamina propria. 8,9,38,41 Other studies have shown that the CX3CR1/ CX3CL1 axis is involved in the pathogenesis of sepsis.…”

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

“…Once neutrophils are present in infected tissues, they employ the numerous effector functions in their arsenal to combat K. pneumoniae infection. Studies using both human neutrophils and mouse models of K. pneumoniae infection have noted the neutrophilic use of a number of processes to contain K. pneumoniae (22,(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171). These processes include phagocytosis/opsonophagocytosis, the production of inflammatory cytokines, and the release of antimicrobial compounds and structures, such as reactive oxygen species, serine proteases (e.g., neutrophil elastase), lactoferrin, lipocalin-2, myeloperoxidase, and neutrophil extracellular traps (NETs), to contain the bacteria and mediate clearance (22,(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171).…”

Distinct Contributions of Neutrophils and CCR2+Monocytes to Pulmonary Clearance of Different Klebsiella pneumoniae Strains

“…There they can become activated to produce tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS) and contribute to microbicidal responses (21). Recently, a potential role for CCR2 ϩ monocytes in defense against Klebsiella pneumoniae was suggested by infection of CCR2 Ϫ/Ϫ mice with K. pneumoniae strain 43816 (22). Here, we have used the murine model of K. pneumoniae infection to investigate the relative contributions of neutrophils and CCR2 ϩ monocytes to pulmonary clearance and survival.…”