Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes
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Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes. / Warszawska, Joanna M; Gawish, Riem; Sharif, Omar; Sigel, Stefanie; Doninger, Bianca; Lakovits, Karin; Mesteri, Ildiko; Nairz, Manfred; Boon, Louis; Spiel, Alexander; Fuhrmann, Valentin; Strobl, Birgit; Müller, Mathias; Schenk, Peter; Weiss, Günter; Knapp, Sylvia.
In: J CLIN INVEST, Vol. 123, No. 8, 01.08.2013, p. 3363-72.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes
AU - Warszawska, Joanna M
AU - Gawish, Riem
AU - Sharif, Omar
AU - Sigel, Stefanie
AU - Doninger, Bianca
AU - Lakovits, Karin
AU - Mesteri, Ildiko
AU - Nairz, Manfred
AU - Boon, Louis
AU - Spiel, Alexander
AU - Fuhrmann, Valentin
AU - Strobl, Birgit
AU - Müller, Mathias
AU - Schenk, Peter
AU - Weiss, Günter
AU - Knapp, Sylvia
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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.
KW - Acute-Phase Proteins
KW - Adult
KW - Aged
KW - Animals
KW - Female
KW - Humans
KW - Immune Tolerance
KW - Interleukin-10
KW - Lipocalins
KW - Lung
KW - Macrophage Activation
KW - Macrophages, Alveolar
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Middle Aged
KW - Oncogene Proteins
KW - Pneumonia, Pneumococcal
KW - Proto-Oncogene Proteins
KW - Transplantation Chimera
U2 - 10.1172/JCI67911
DO - 10.1172/JCI67911
M3 - SCORING: Journal article
C2 - 23863624
VL - 123
SP - 3363
EP - 3372
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 8
ER -