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 1

LCN2 is highly expressed in deactivated macrophages.

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LCN2 is highly expressed in deactivated macrophages. (A) Primary AMs wer...
(A) Primary AMs were polarized with M1 (100 ng/ml LPS, 200 U/ml IFN-γ), M2 (10 ng/ml IL-4 and IL-13), or deactivating (Mdx; 10 ng/ml LPS, 100 μM dexamethasone) stimuli for 16 hours. Nitrite and LCN2 were measured in supernatants using the Griess reagent or ELISA. Mrc1 mRNA levels were determined using qRT-PCR, normalized to HPRT, and expressed as fold change relative to control cells. (B and C) Primary AMs were treated with 4 × 107 CFU/ml S. pneumoniae or 10 ng/ml LPS with or without defined deactivating stimuli (10 ng/ml IL-10, 100 μM dexamethasone, or 107/ml ACs) for 16 hours. LCN2 (B) and KC (C) levels were quantified in supernatants using ELISA. (D and E) BMDMs were polarized with M1 (10 ng/ml LPS, 200 U/ml IFN-γ) or M2 (10 ng/ml IL-4 and IL-13), activated with 10 ng/ml LPS (Mx), or deactivated (Mdx) with 10 ng/ml LPS and 100 μM dexamethasone (D and E) or 10 ng/ml IL-10 (D) for 1, 6, and 16 hours. LCN2 (D) and IL-10 (E) levels were assessed in supernatants using ELISA. Data are presented as mean ± SEM of quadruplicates and are representative of 2 independent experiments. n.d., not detectable. **P < 0.001, #P < 0.0001 versus M0 (A; ANOVA) or S. pneumoniae or LPS alone (B and C; ANOVA).