Lipocalin 2 prevents intestinal inflammation by enhancing phagocytic bacterial clearance in macrophages

Toyonaga, Takahiko; Matsuura, Minoru; Mori, Kiyoshi; Honzawa, Yusuke; Minami, Naoki; Yamada, Satoshi; Kobayashi, Taku; Hibi, Toshifumi; Nakase, Hiroshi

doi:10.1038/srep35014

Cited by 50 publications

(38 citation statements)

References 50 publications

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“…However, at sacrifice both ADR-159 and standard-fed animals had elevated levels of fecal LCN2. LCN2 is commonly used as a sensitive inflammation indicator (Chassaing et al, 2012), yet it has been shown that LCN2 itself has a role in prevention of intestinal inflammation by enhancing pathogen clearance in macrophages (Toyonaga et al, 2016). Nonetheless, these findings suggest that localized Citrobacterinduced inflammation is lower in ADR-159 fed animals and has potentially a later onset (alternatively LCN2 response is delayed due to the lower initial inflammation), compared to standard fed animals.…”

Section: Effect Of Adr-159 On Citrobacter-induced Colitismentioning

confidence: 99%

Oral Administration of Heat-Treated Lactobacilli Modifies the Murine Microbiome and Reduces Citrobacter Induced Colitis

et al. 2020

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Significant evidence supports a relationship between the gut microbiome, inflammation, host response, and health, including the finding that a number of disorders are associated with disruption of the microbiome. In these disorders, a number of dietary interventions (including prebiotics, live probiotics, or heat-killed microbes) have been proposed to be curative or preventative agents. The use of heat-killed microbes has a number of benefits over living organisms, including reduced infection risk in vulnerable individuals, extended shelf life and the potential for use in combination with antimicrobial agents. We previously reported that murine chow supplemented with 5% ADR-159, a heat-treated fermentate generated by two Lactobacillus strains, altered both behavior and the microbiome of male mice. Now we show that ADR-159 fed female mice also display a similar microbiome shift as determined by 16S rDNA analysis. In particular, we observed a reduction of levels of Turicibacter and Clostridium sensu stricto. These subtle changes in the bacterial component of the microbiome were mirrored by changes in the virome. Extended consumption of the ADR-159 diet had no negative effect on general health and lipocalin 2 levels (LCN2; a proxy for inflammation), but we observed increased IL-17f and decreased IL-12α expression in the colon and decreased short chain fatty acid levels in the ADR-159 fed animals. Four weeks into the diet, half of the animals were dosed with Citrobacter to determine the effect of ADR-159 on infection and on pathogen induced colitis. Overall, our results suggest that while the ADR-159 diet does not prevent Citrobacter infection, it had an effect on Citrobacter-induced inflammation. In contrast to animals fed standard chow, ADR-159 fed animals did not show a reduction of small intestine length and increase of colon crypt depth, which occurred in control mice. These microbiological, histological, and immunological results provide evidence to support the impact of heat-treated microorganisms and their metabolites on the murine microbiome and health.

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Section: Effect Of Adr-159 On Citrobacter-induced Colitismentioning

confidence: 99%

Oral Administration of Heat-Treated Lactobacilli Modifies the Murine Microbiome and Reduces Citrobacter Induced Colitis

et al. 2020

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“…Acting as an anti-microbial acute phase reactant, the levels of lipocalin 2 (mouse Lcn2/human LCN2) are increased to limit the growth of pathogens upon infection [11]. Lipocalin 2 could be one of the mediators in the gut-joint axis, owing to its pleiotropic properties in inflammation and bone remodeling [12,13]. It is produced by multiple cell types in different tissues, including the gut and joint [14,15].…”

Section: Introductionmentioning

confidence: 99%

Lipocalin 2 links inflammation and ankylosis in the clinical overlap of inflammatory bowel disease (IBD) and ankylosing spondylitis (AS)

et al. 2020

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Background: Little is known about the mechanisms underlying the clinical overlap between gut inflammation and joint ankylosis, as exemplified by the concurrence of inflammatory bowel diseases (IBD) and ankylosing spondylitis (AS). As dysbiosis may serve as a common contributor, the anti-microbial pleiotropic factor lipocalin 2 could be a potential mediator due to its roles in inflammation and bone homeostasis. Methods: Baseline colonic pathology was conducted in the ank/ank mouse model. Serum lipocalin 2 was analyzed by ELISA, in ank/ank mutants versus C3FeB6-A/A w-j wt/wt, in patients with concurrent AS-IBD, AS alone, IBD alone, or mechanical back pain, and in healthy controls. In the ank/ank mouse model, the expression of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) was examined by real-time PCR. Intraperitoneal injection was done with the PPARγ agonist rosiglitazone or antagonist bisphenol A diglycidyl ether for four consecutive days. Serum levels of lipocalin 2 were examined on the sixth day. Results: This study showed that the ank/ank mice with fully fused spines had concurrent colonic inflammation. By first using the ank/ank mouse model with progressive ankylosis and subclinical colonic inflammation, confirmed in patients with concurrent AS and IBD, elevated circulating lipocalin 2 levels were associated with the coexisting ankylosis and gut inflammation. The intracellular pathway of lipocalin 2 was further investigated with the ank/ank mouse model involving PPARγ. Colonic expression of PPARγ was negatively associated with the degree of gut inflammation. The PPARγ agonist rosiglitazone treatment significantly upregulated the serum levels of lipocalin 2, suggesting a potential regulatory role of PPARγ in the aberrant expression of lipocalin 2. Conclusions: In summary, lipocalin 2 modulated by PPARγ could be a potential pathway involved in concurrent inflammation and ankylosis in AS and IBD.

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“…Binding of Lcn2 to its receptor 24p3R was also shown to be an important event that activated subsequent apoptosis (Devireddy, Gazin, Zhu, & Green, ; Goetz et al, ; Yang et al, ). Due to its crucial roles, knockout of Lcn2 resulted in high susceptibility and higher mortality rates in E. coli than the wild‐type strain in mice (Toyonaga et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…Due to its crucial roles, knockout of Lcn2 resulted in high susceptibility and higher mortality rates in E. coli than the wild-type strain in mice (Toyonaga et al, 2016).…”

mentioning

confidence: 99%

Lipocalin 2 (Lcn2) interferes with iron uptake byBrucella abortusand dampens immunoregulation during infection of RAW 264.7 macrophages

Hop

Arayan

Huy

et al. 2017

Cellular Microbiology

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Lipocalin 2 (Lcn2) is an important innate immunity component against bacterial pathogens. In this study, we report that Lcn2 is induced by Brucella (B.) abortus infection and significantly contributes to the restriction of intracellular survival of Brucella in macrophages. We found that Lcn2 prevented iron uptake by B. abortus through two distinct mechanisms. First, Lcn2 is secreted to capture bacterial siderophore(s) and abrogate iron import by Brucella. Second, Lcn2 decreases the intracellular iron levels during Brucella infection, which probably deprives the invading Brucella of the iron source needed for growth. Suppression of Lcn2 signalling resulted in a marked induction of anti-inflammatory cytokine, interleukin 10, which was shown to play a major role in Lcn2-induced antibrucella immunity. Similarly, interleukin 6 was also found to be increased when Lcn2 signalling is abrogated; however, this induction was thought to be an alternative pathway that rescues the cell from infection when the effective Lnc2 pathway is repressed. Furthermore, Lcn2 deficiency also caused a marked decrease in brucellacidal effectors, such as reactive oxygen species and nitric oxide but not the phagolysosome fusion. Taken together, our results indicate that Lcn2 is required for the efficient restriction of intracellular B. abortus growth that is through limiting iron acquisition and shifting cells to pro-inflammatory brucellacidal activity in murine macrophages.

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Lipocalin 2 prevents intestinal inflammation by enhancing phagocytic bacterial clearance in macrophages

Cited by 50 publications

References 50 publications

Oral Administration of Heat-Treated Lactobacilli Modifies the Murine Microbiome and Reduces Citrobacter Induced Colitis

Oral Administration of Heat-Treated Lactobacilli Modifies the Murine Microbiome and Reduces Citrobacter Induced Colitis

Lipocalin 2 links inflammation and ankylosis in the clinical overlap of inflammatory bowel disease (IBD) and ankylosing spondylitis (AS)

Lipocalin 2 (Lcn2) interferes with iron uptake byBrucella abortusand dampens immunoregulation during infection of RAW 264.7 macrophages

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