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.

Bacterial Siderophores That Evade or Overwhelm Lipocalin 2 Induce Hypoxia Inducible Factor 1α and Proinflammatory Cytokine Secretion in Cultured Respiratory Epithelial Cells

“…We hypothesize that the difference in outcome is because Streptococcus pneumoniae does not require siderophores for its pathogenesis, and Lcn2 cannot properly modulate inflammation during infection without siderophore-mediated iron chelation. In fact, patient survival from Gram-negative pneumonia correlated with increased Lcn2 in the bronchoalveolar lavage fluid (49).…”

“…In recent work, stimulation of macrophages with Streptococcus pneumoniae induced IL-10 production in an Lcn2-dependent manner, which skewed macrophages toward a deactivated phenotype (49). In human and animal models, increased Lcn2 correlated with worsening of pneumococcal pneumonia.…”

Lipocalin 2 Regulates Brown Fat Activation via a Nonadrenergic Activation Mechanism

“…Because Lcn2 has been implicated in the regulation of immune response (25,35), we sought to address whether inflammatory signaling is changed in BAT of Lcn2 Ϫ/Ϫ mice serving as a potential mechanism. In the first experiment, we examined the expression of M2 and M1 macrophage markers in BAT of mice in response to cold exposure.…”

Epinecidin-1 Has Immunomodulatory Effects, Facilitating Its Therapeutic Use in a Mouse Model of Pseudomonas aeruginosa Sepsis

“…The A3-APO dimer is thought to be degraded into shorter fragments within the mouse body, generating the active metabolite (37). Most peptides, including defensins, protegrins, and clavanins, are inactivated in the presence of blood or have reduced antimicrobial activities at pHs of Ͻ7 (38,39). Proteolytic degradation and sequestration by serum are two major hurdles for the in vivo application of AMPs (40).…”