Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes
Joanna M. Warszawska, Riem Gawish, Omar Sharif, Stefanie Sigel, Bianca Doninger, Karin Lakovits, Ildiko Mesteri, Manfred Nairz, Louis Boon, Alexander Spiel, Valentin Fuhrmann, Birgit Strobl, Mathias Müller, Peter Schenk, Günter Weiss, Sylvia Knapp
Joanna M. Warszawska, Riem Gawish, Omar Sharif, Stefanie Sigel, Bianca Doninger, Karin Lakovits, Ildiko Mesteri, Manfred Nairz, Louis Boon, Alexander Spiel, Valentin Fuhrmann, Birgit Strobl, Mathias Müller, Peter Schenk, Günter Weiss, Sylvia Knapp
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Research Article Immunology

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

Abstract

Macrophages play a key role in responding to pathogens and initiate an inflammatory response to combat microbe multiplication. Deactivation of macrophages facilitates resolution of the inflammatory response. Deactivated macrophages are characterized by an immunosuppressive phenotype, but the lack of unique markers that can reliably identify these cells explains the poorly defined biological role of this macrophage subset. We identified lipocalin 2 (LCN2) as both a marker of deactivated macrophages and a macrophage deactivator. We show that LCN2 attenuated the early inflammatory response and impaired bacterial clearance, leading to impaired survival of mice suffering from pneumococcal pneumonia. LCN2 induced IL-10 formation by macrophages, skewing macrophage polarization in a STAT3-dependent manner. Pulmonary LCN2 levels were tremendously elevated during bacterial pneumonia in humans, and high LCN2 levels were indicative of a detrimental outcome from pneumonia with Gram-positive bacteria. Our data emphasize the importance of macrophage deactivation for the outcome of pneumococcal infections and highlight the role of LCN2 and IL-10 as determinants of macrophage performance in the respiratory tract.

Authors

Joanna M. Warszawska, Riem Gawish, Omar Sharif, Stefanie Sigel, Bianca Doninger, Karin Lakovits, Ildiko Mesteri, Manfred Nairz, Louis Boon, Alexander Spiel, Valentin Fuhrmann, Birgit Strobl, Mathias Müller, Peter Schenk, Günter Weiss, Sylvia Knapp

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Figure 6

LCN2 impairs bacterial clearance in an IL-10–dependent manner.

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LCN2 impairs bacterial clearance in an IL-10–dependent manner. (A) KC le...
(A) KC levels in supernatants of WT BMDMs stimulated with 4 × 107 CFU/ml S. pneumoniae with or without 100 ng/ml LCN2 and with or without 10 μg/ml anti–IL-10 or isotype control antibody for 6 hours. (B) Normalized KC secretion from WT, STAT3+/+, and STAT3fl/fl BMDMs treated with 4 × 107 CFU/ml S. pneumoniae plus LCN2 (100 ng/ml) or IL-10 (10 ng/ml) for 6 hours. (C) RAW264.7 overexpressing LCN2 or GFP, transfected with an IL-10 reporter and stimulated with 4 × 107 CFU/ml S. pneumoniae for 24 hours. Reporter gene activity was measured in cell lysates and normalized to Renilla. (D) WT BMDMs were treated with 4 × 107 CFU/ml S. pneumoniae plus LCN2 (0.1 μg/ml and 1 μg/ml) for 6 hours. IL-10 release was measured in supernatants using ELISA. (E–G) WT and Lcn2–/– mice were intranasally infected with 105 CFU S. pneumoniae, followed by intranasal administration of 150 μg anti–IL-10 mAb or isotype control Ab. (E and F) Bacterial counts in lung (E) and blood (F) were quantified 48 hours after infection. (G) IL-6 secretions in lung homogenates were determined using ELISA. Data are presented as mean ± SEM (n = 4 [A–D]; 8 [E–G] per group). *P < 0.05, **P < 0.001, #P < 0.0001 versus S. pneumoniae alone (A, B, and D; ANOVA), GFP control (C; t test), or WT (E and G; ANOVA).