Lipocalin-2 protects the brain during inflammatory conditions

Abstract

Sepsis is a prevalent health issue that can lead to central nervous system (CNS) inflammation with long-term behavioral and cognitive alterations. Using unbiased proteomic profiling of over 100 different cytokines, we found that Lipocalin-2 (LCN2) was the most substantially elevated protein in the CNS after peripheral administration of lipopolysaccharide (LPS). To determine whether the high level of LCN2 in the CNS is protective or deleterious, we challenged Lcn2−/− mice with peripheral LPS and determined effects on behavior and neuroinflammation. At a time corresponding to peak LCN2 induction in WT mice injected with LPS, Lcn2−/− mice challenged with LPS had exacerbated levels of pro-inflammatory cytokines and exhibited significantly worsened behavioral phenotypes. To determine the extent of global inflammatory changes dependent upon LCN2, we performed an RNAseq transcriptomic analysis. Compared to WT mice injected with LPS, Lcn2−/− mice injected with LPS had unique transcriptional profiles and significantly elevated levels of multiple pro-inflammatory molecules. Several LCN2-dependent pathways were revealed with this analysis including, cytokine and chemokine signaling, NOD-like receptor signaling, and Jak-STAT signaling. These findings demonstrate that LCN2 serves as a potent protective factor in the CNS in response to systemic inflammation and may be a potential candidate for limiting sepsis-related CNS sequelae.

Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1

“…These include C4b , a complement component and marker of astrocyte activation and aging (Boisvert et al, 2018; Clarke et al, 2018), Megf10 , which mediates astrocytic synapse elimination (Chung et al, 2013), and Pla2g3 , a phospholipase implicated in ROS-induced neuronal damage (Martínez-García et al, 2010). Activation marker Lcn2 (lipocalin 2), an anti-inflammatory mediator in the brain (Kang et al, 2018), was not increased, again suggesting a pro-inflammatory state.…”

Lipocalin 2 Suppresses Ocular Inflammation by Inhibiting the Activation of NF-κβ Pathway in Endotoxin-Induced Uveitis

“…Previous studies have shown that after LPS stimulation, Lcn2 as an acute phase protein is rapidly induced in various cells of the central nervous system, including astrocytes, microglia and endothelial cells [31-33]. Moreover, the expression of LCN2 was found to be markedly elevated in the brain and in cultured astrocytes at 4–8 h after exposure to an inflammatory stimulus [19, 34, 35]. Similar to these studies, we found that LCN2 protein levels in retinal tissues and in cultured Müller cells were significantly increased at 8 h after LPS treatment, suggesting that LCN2 is likely to be involved in the early response to inflammatory stimuli.…”

“…It is widely known that LCN2 plays various biological roles in cell survival, apoptosis and iron transport [36]. Previous studies have shown that LCN2 is an important mediator in the regulation of a range of inflammatory diseases, including sepsis, inflammatory bowel disease, and in inflammatory disorders of the central nervous system [19, 37, 38]. However, the specific roles of LCN2 in different inflammatory conditions are not always consistent.…”

“…For example, Nam et al found that LCN2 acted in a proinflammatory manner in experimental autoimmune encephalomyelitis models of neuroinflammation [39], and Jang et al reported that Lcn2 –/– mice had reduced brain IL-12, TNF-α, and IL-23 mRNA levels after LPS injection, suggesting a proinflammatory role LCN2 in the central nervous system [32]. In contrast, Kang et al found that Lcn2 –/– mice treated with LPS had significantly elevated levels of proinflammatory cytokines and displayed worse behavioral performance than normal mice [19]. The anti-inflammatory actions of LCN2 are also supported by the finding of Zhang et al that LCN2 reduced the LPS-induced expression of cytokines by RAW264.7 macrophages [40].…”

“…However, conflicting roles for LCN2 in different inflammatory diseases have been reported. Several in vivo studies reported that LCN2 drives the inflammatory responses in pneumonia, psoriasis, and Alzheimer’s disease [16-18], whereas other studies have demonstrated that LCN2 exerts an anti-inflammatory activity in sepsis, tuberculosis, and autoimmune encephalomyelitis [19-21]. However, there have been few studies of the role of LCN2 in ocular diseases, especially uveitis.…”