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

Abstract

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.

Lipocalin 2 modulates the cellular response to amyloid beta

“…26 Production of LCN2 by astrocytes was previously described both in vitro, in response to proinflammatory cytokines such as interferon-g and TNF, 17,26 and in vivo, in models of CNS neuroinflammatory diseases like experimental autoimmune encephalomyelitis 19 and spinal cord injury. 27 Interestingly, also microglial cells were shown to respond to LCN2, which seems to favor their polarization into a M1-activated phenotype. 28 Here, we show that LCN2 is not produced by microglia in response to Ab , both in astrocyte-enriched cultures (o5% microglia) and in microglia-enriched cultures.…”

Role of Lipocalin-2 in Brain Injury after Intracerebral Hemorrhage

“…Although LCN2 is considered as being mainly expressed in astrocytes, 12,14,23,24 where its secretion may be neurotoxic, 24 other cell types may express LCN2. Thus, inflammatory cells, such as microglia and neutrophils 15,25,26 can also express LCN2. The effects of LCN2 on microglia are complex.…”

“…15 Inflammation has an important role in ICH-induced brain injury. 16 This study investigates the effect LCN2 deficiency on the expression of ferritin (an iron storage protein), microglia activation, neuronal death, and neurologic deficits in a mouse model of ICH.…”

Lipocalin comes callin’ on the hippocampus

“…Indeed, there are already data suggesting that the role played by Lcn-2 often varies with the context in which it is being activated. For example, after spinal cord injury, Lcn-2 protein level is enhanced rapidly (18). However, in this case Lcn-2 has been shown to have detrimental effects after injury, and the lack of Lcn-2 actually improves locomotor recovery after injury (18).…”

“…For example, after spinal cord injury, Lcn-2 protein level is enhanced rapidly (18). However, in this case Lcn-2 has been shown to have detrimental effects after injury, and the lack of Lcn-2 actually improves locomotor recovery after injury (18). Similarly, Lcn-2 expression and secretion is enhanced after inflammatory stimulation in cultured astrocytes (19).…”