Lipocalin 2 Deficiency Dysregulates Iron Homeostasis and Exacerbates Endotoxin-Induced Sepsis

Srinivasan, Gayathri; Aitken, Jesse D.; Zhang, Benyue; Carvalho, Frédéric A.; Chassaing, Benoît; Shashidharamurthy, Rangaiah; Borregaard, Niels; Jones, Dean P.; Gewirtz, Andrew T.; Vijay‐Kumar, Matam

doi:10.4049/jimmunol.1200892

Cited by 114 publications

(109 citation statements)

References 56 publications

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“…In accordance with our data, Zhang et al reported that LCN2 reduced the LPStriggered induction of cytokines by RAW264.7 macrophages (24). During completion of this manuscript, another group reported enhanced levels of LPS-induced proinflammatory cytokines secreted by LCN2-deficient peritoneal macrophages and BMDMs as compared with WT cells (42). However, in contrast to our data, this report also showed increased IL-10 releases by Lcn2 -/-peritoneal macrophages, which might be due to differences specific to macrophage subset or the fact that we focused on S. pneumoniae.…”

Section: Discussionsupporting

confidence: 76%

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

Warszawska¹,

Gawish²,

Sharif³

et al. 2013

J. Clin. Invest.

124

123

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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.

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Section: Discussionsupporting

confidence: 76%

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

Warszawska¹,

Gawish²,

Sharif³

et al. 2013

J. Clin. Invest.

124

123

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“…Elevated serum NGAL concentrations in sepsis could be attributed to the systemic launch of different inflammatory mechanisms activating local or distant neutrophils, macrophages, and other immune cells, dampening the inflammatory response (18). A major mechanism of de novo upregulation involves fundamental upstream inflammatory pathways, including signaling via Toll-like receptor 4 activated by lipopolysaccharide (19).…”

Section: Discussionmentioning

confidence: 99%

Increased Neutrophil Gelatinase–Associated Lipocalin is Associated with Mortality and Multiple Organ Dysfunction Syndrome in Severe Sepsis and Septic Shock

Wang

Chen

Zhang

et al. 2015

Shock

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“…However, studies also showed that LCN2 can regulate the intracellular iron concentration and LCN2 deficiency can increase the cellular iron levels in sepsis. 30 Thus, the role of LCN2 in iron transport still need further study.…”

Section: Discussionmentioning

confidence: 99%

Role of Lipocalin-2 in Brain Injury after Intracerebral Hemorrhage

Zheng

et al. 2015

J Cereb Blood Flow Metab

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Lipocalin-2 (LCN2) is a siderophore-binding protein involved in cellular iron transport and neuroinflammation. Both iron and inflammation are involved in brain injury after intracerebral hemorrhage (ICH) and this study examined the role of LCN2 in such injury. Male adult C57BL/6 wild-type (WT) or LCN2-deficient (LCN2 − / − ) mice had an intracerebral injection of autologous blood or FeCl 2 . Control animals had a sham operation or saline injection. T2-weighted magnetic resonance imaging and behavioral tests were performed at days 1, 3, 7, 14, and 28 after injection. In WT mice, brain LCN2 levels were increased in the ipsilateral basal ganglia after ICH or iron injection. Lipocalin-2-positive cells were astrocytes, microglia, neurons, and endothelial cells. Intracerebral hemorrhage resulted in a significant increase in ferritin expression in the ipsilateral basal ganglia. Compared with WT mice, ICH caused less ferritin upregulation, microglia activation, brain swelling, brain atrophy, and neurologic deficits in LCN2− / − mice (P o0.05). The size of the lesion induced by FeCl 2 injection as well as the degree of brain swelling and blood-brain barrier disruption were also less in LCN2− / − mice (P o 0.05). These results suggest a role of LCN2 in enhancing brain injury and iron toxicity after ICH.

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Lipocalin 2 Deficiency Dysregulates Iron Homeostasis and Exacerbates Endotoxin-Induced Sepsis

Cited by 114 publications

References 56 publications

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

Increased Neutrophil Gelatinase–Associated Lipocalin is Associated with Mortality and Multiple Organ Dysfunction Syndrome in Severe Sepsis and Septic Shock

Role of Lipocalin-2 in Brain Injury after Intracerebral Hemorrhage

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