Granulocyte-Macrophage Colony-Stimulating Factor in the Innate Immune Response toPneumocystis cariniiPneumonia in Mice

Abstract

Innate immunity plays an important role in pulmonary host defense against Pneumocystis carinii, an important pathogen in individuals with impaired cell-mediated immunity. We investigated the role of GM-CSF in host defense in a model of P. carinii pneumonia induced by intratracheal inoculation of CD4-depleted mice. Lung GM-CSF levels increased progressively during the infection and were significantly greater than those in uninfected controls 3, 4, and 5 wk after inoculation. When GM-CSF gene-targeted mice (GM ؊/؊ ) depleted of CD4 ؉ cells were inoculated with P. carinii, the intensities of infection and inflammation were increased significantly compared with those in CD4-depleted wild-type mice. In contrast, transgenic expression of GM-CSF directed solely in the lungs of GM ؊/؊ mice (using the surfactant protein C promoter) dramatically decreased the intensity of infection and inflammation 4 wk after inoculation. The concentrations of surfactant proteins A and D were greater in both uninfected and infected GM ؊/؊ mice compared with those in wild-type controls, suggesting that this component of the innate response was preserved in the GM ؊/؊ mice. However, alveolar macrophages (AM) from GM ؊/؊ mice demonstrated impaired phagocytosis of purified murine P. carinii organisms in vitro compared with AM from wild-type mice. Similarly, AM production of TNF-␣ in response to P. carinii in vitro was totally absent in AM from GM ؊/؊ mice, while GM-CSF-replete mice produced abundant TNF in this setting. Thus, GM-CSF plays a critical role in the inflammatory response to P. carinii in the setting of impaired cell-mediated immunity through effects on AM activation.

Granulocyte–macrophage colony stimulating factor-mediated innate responses in tuberculosis

“…Consistent with this notion, the intravenous administration of non-degradable pegylated GM-CSF resulted in high dendritic cell numbers that, paradoxically, increased the susceptibility of the mice to Listeria monocytogenes and M. tuberculosis despite elevated adaptive responses. 30 While previous studies demonstrated that GM-CSF levels in the lung influence the clearance rate of a number of pulmonary infections, [20][21][22][23] the present study reports that GM-CSF levels do not influence the clearance of the attenuated Mycobacterium bovis BCG or the establishment of the virulent M. tuberculosis H37Rv. Our results in GM-CSF −/− mice demonstrate that GM-CSF has a critical early role in preserving the integrity of alveolar epithelial cells in the presence of virulent M. tuberculosis infection.…”

“…Based on the above findings and previous results showing that lung GM-CSF significantly alters infection levels in the lungs, [20][21][22] we then tested the hypothesis that high-dose mycobacterial infection would be cleared differently from the lungs of WT, GMKO, and GMOE mice. On the contrary, Figure 2A demonstrates that both the early clearance and persistence of pulmonary BCG was similar in all mice.…”

“…[20][21][22][23] The studies in the present report determined the effect of GM-CSF expression pulmonary mycobacterial infections. Previous studies reported lung-specific arrest in functional activation of alveolar macro-phages marked by depression of innate immune responses including phagocytosis and cytokine secretion in GMKO mice.…”

“…Thus, the higher expression of innate receptors in GMOE alveolar macrophages may contribute to the enhanced ability of GMOE mice to reduce the burden of infection even more efficiently than WT mice. [20][21][22] Because MARCO is also highly expressed in spleen, we assessed local versus peripheral effects of lung GM-CSF expression ( Figure 1B). In contrast to lung, MARCO is expressed in the spleens of GMKO mice indicating that the impact of GM-CSF deficiency on macro-phage differentiation is lung-specific.…”

“…10,11 Absence or blockade of GM-CSF decreases pulmonary surfactant catabolism, [12][13][14][15][16][17] reduces alveolar macrophage functions, 10,18,19 and increases susceptibility to infections. [20][21][22][23][24] Complementary studies that assessed the ability of lungspecific expression of GM-CSF to restore pulmonary homeostasis in mice led to the unexpected discovery that GM-CSF influences the proliferation of alveolar Type II epithelial cells, which were shown to express the GM-CSF receptor a subunit. 25 The loss of GM-CSF signaling manifests as pulmonary alveolar proteinosis (PAP) in both mice and humans.…”