M-CSF Mediates Host Defense during Bacterial Pneumonia by Promoting the Survival of Lung and Liver Mononuclear Phagocytes

Abstract

Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. Macrophage-colony stimulating factor (M-CSF) has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, the proliferation of precursors or the recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and anti-microbial functions of both lung and liver mononuclear phagocytes during pneumonia and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and anti-microbial functions of mononuclear phagocytes in the lungs and liver.

Emerging roles of IL-34 in health and disease

“…2 A). While most of these studies reported gene expression, IL-34 protein was described in the healthy murine lung and human skin, kidney, intestine, spleen, and brain (Baek et al, 2015;Bettina et al, 2016;Franzè et al, 2015;Greter et al, 2012;Lin et al, 2008). We also found that IL-34 protein was detectable across various mouse tissues, with highest expression in brain, skin, and lymph nodes ( Fig.…”

<b><i>Pseudomonas aeruginosa</i></b> and <b><i>Klebsiella</i></b> <b><i>pneumoniae</i></b> Adaptation to Innate Immune Clearance Mechanisms in the Lung

“…Alveolar macrophages, the resident responders to pathogens in the airways, are critical to the clearance of K. pneumoniae pneumonia [107, 108]. The activation state and polarization of these macrophages are important in this process, as macrophages in the M2b or anti-inflammatory state were more susceptible to infection [109, 110].…”

Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia

“…We used a well-described model of Klebsiella pneumonia caused by a virulent strain of bacteria, delivered directly into the trachea of sedated experimental mice (15,16). We first characterized the effect of Klebsiella pneumonia on iron metabolism in WT mice.…”

“…Experimental bacterial pneumonia was induced as previously described (15,16), by intratracheal inoculation of 500-1,500 CFU of K. pneumoniae strain 43816 (American Type Culture Collection). In some experiments, 1,500 CFU of K. pneumoniae was delivered i.v.…”

“…Cell suspensions from blood and BAL fluid were prepared and analyzed by flow cytometry as previously described, with minor modifications (16,63,64). The following antibodies were used for surface antigen staining: anti-MHC-II APC (clone M5/114.15.2), anti-CD11b Pe-Cy7 (clone M170), and anti-CD115 APC (clone AF598) from eBioscience; anti-CD11c PerCP (clone HL3) and anti-CD64 brilliant violet 421 (clone X54-5/7.1) from BioLegend; and anti-CD16/CD32 (clone 2.4G2), anti-Ly6G PE (clone 1A8), and anti-CD45 AmCyan (clone 30-F11) from BD Biosciences.…”