Absence of functional Hfe protects mice from invasive Salmonella enterica Serovar Typhimurium infection via induction of lipocalin-2

Nairz, Manfred; Theurl, Igor; Schroll, Andrea; Theurl, Milan; Fritsche, Gernot; Lindner, Ewald; Seifert, Markus; Crouch, Marie Laure V; Hantke, Klaus; Akira, Shizuo; Fang, Ferric C.; Weiss, Günter

doi:10.1182/blood-2009-05-223354

Cited by 135 publications

(169 citation statements)

References 55 publications

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“…The role of Lcn2 as part of the innate immune system defense against bacteria and pathogens is becoming better defined (Flo et al, 2004;Saiga et al, 2008;Chan et al, 2009;Nairz et al, 2009). However, its role in other inflammatory diseases and traumatic injuries has not been thoroughly examined.…”

Section: Discussionmentioning

confidence: 99%

Lipocalin 2 Plays an Immunomodulatory Role and Has Detrimental Effects after Spinal Cord Injury

Rathore¹,

Berard²,

Redensek³

et al. 2011

J. Neurosci.

113

110

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Lipocalin 2 (Lcn2) plays an important role in defense against bacterial infection by interfering with bacterial iron acquisition. Although Lcn2 is expressed in a number of aseptic inflammatory conditions, its role in these conditions remains unclear. We examined the expression and role of Lcn2 after spinal cord injury (SCI) in adult mice by using a contusion injury model. Lcn2 expression at the protein level is rapidly increased 12-fold at 1 d after SCI and decreases gradually thereafter, being three times as high as control levels at 21 d after injury. Lcn2 expression is strongly induced after contusion injury in astrocytes, neurons, and neutrophils. The Lcn2 receptor (Lcn2R), which has been shown to influence cell survival, is also expressed after SCI in the same cell types. Lcn2-deficient (Lcn2 ؊/؊ ) mice showed significantly better locomotor recovery after spinal cord contusion injury than wild-type (Lcn2 ؉/؉ ) mice. Histological assessments indicate improved neuronal and tissue survival and greater sparing of myelin in Lcn2 ؊/؊ mice after contusion injury. Flow cytometry showed a decrease in neutrophil influx and a small increase in the monocyte population in Lcn2 ؊/؊ injured spinal cords. This change was accompanied by a reduction in the expression of several pro-inflammatory chemokines and cytokines as well as inducible nitric oxide synthase early after SCI in Lcn2 ؊/؊ mice compared with wild-type animals. Our results, therefore, suggest a role for Lcn2 in regulating inflammation in the injured spinal cord and that lack of Lcn2 reduces secondary damage and improves locomotor recovery after spinal cord contusion injury.

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Section: Discussionmentioning

confidence: 99%

Lipocalin 2 Plays an Immunomodulatory Role and Has Detrimental Effects after Spinal Cord Injury

Rathore¹,

Berard²,

Redensek³

et al. 2011

J. Neurosci.

113

110

View full text Add to dashboard Cite

show abstract

“…Wild-type (WT) and Lcn2 KO mice were backcrossed for 8-10 generations in a C57BL/6 background to generate homozygous and heterozygous animals, as described previously (17,40). Genotypes were confirmed by PCR of genomic DNA (40).…”

Section: Mouse Breeding and Maintenancementioning

confidence: 99%

Phenotypic Polarization of Activated Astrocytes: The Critical Role of Lipocalin-2 in the Classical Inflammatory Activation of Astrocytes

Jang

Kim

Lee

et al. 2013

The Journal of Immunology

188

157

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Astrocytes provide structural and functional support for neurons, as well as display neurotoxic or neuroprotective phenotypes depending upon the presence of an immune or inflammatory microenvironment. This study was undertaken to characterize multiple phenotypes of activated astrocytes and to investigate the regulatory mechanisms involved. We report that activated astrocytes in culture exhibit two functional phenotypes with respect to pro- or anti-inflammatory gene expression, glial fibrillary acidic protein expression, and neurotoxic or neuroprotective activities. The two distinct functional phenotypes of astrocytes were also demonstrated in a mouse neuroinflammation model, which showed pro- or anti-inflammatory gene expression in astrocytes following challenge with classical or alternative activation stimuli; similar results were obtained in the absence of microglia. Subsequent studies involving recombinant lipocalin-2 (LCN2) protein treatment or Lcn2-deficient mice indicated that the pro- or anti-inflammatory functionally polarized phenotypes of astrocytes and their intracellular signaling pathway were critically regulated by LCN2 under in vitro and in vivo conditions. Astrocyte-derived LCN2 promoted classical proinflammatory activation of astrocytes but inhibited IL-4–STAT6 signaling, a canonical pathway involved in alternative anti-inflammatory activation. Our results suggest that the secreted protein LCN2 is an autocrine modulator of the functional polarization of astrocytes in the presence of immune or inflammatory stimuli and that LCN2 could be targeted therapeutically to dampen proinflammatory astrocytic activation and related pathologies in the CNS.

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“…For survival studies, sex-and age-matched mice were infected i.p. with 200 CFUs of Salmonella diluted in 200 ml of PBS (Nairz et al, 2009b). Mice were monitored twice daily until death, and after 336 hours, the experiments were terminated.…”

Section: Salmonella Infection In Vivomentioning

confidence: 99%

The late endosomal adaptor p14 is a macrophage host defense factor against Salmonella Typhimurium infection

Taub

Nairz

Hilber

et al. 2012

Journal of Cell Science

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SummaryThe outcome of an infection depends on the balance between host resistance and bacterial virulence. Here, we show that the late endosomal adaptor p14 (also known as LAMTOR2) is one of the components for cellular host defense against the intracellular pathogen Salmonella enterica serovar Typhimurium. During Salmonella infection, the complex of p14 and MP1 is required for the accurately timed transport of Salmonella through the endolysosomal system. Loss of p14 opens a time window that allows Salmonella to populate a replication niche, in which early and late antimicrobial effector systems, comprising NADPH phagocytic oxidase and inducible nitric oxide synthase, respectively, are inappropriately activated. Thus, p14 supports the accurate transport of Salmonella through the endolysosomal system, thereby limiting bacterial replication in both, professional phagocytes and in non-phagocytic cells in vitro, and helps mice to successfully battle Salmonella infection in vivo.

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Absence of functional Hfe protects mice from invasive Salmonella enterica Serovar Typhimurium infection via induction of lipocalin-2

Cited by 135 publications

References 55 publications

Lipocalin 2 Plays an Immunomodulatory Role and Has Detrimental Effects after Spinal Cord Injury

Lipocalin 2 Plays an Immunomodulatory Role and Has Detrimental Effects after Spinal Cord Injury

Phenotypic Polarization of Activated Astrocytes: The Critical Role of Lipocalin-2 in the Classical Inflammatory Activation of Astrocytes

The late endosomal adaptor p14 is a macrophage host defense factor against Salmonella Typhimurium infection

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