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Cited by 147Iron Metabolism and DisordersInfant Nutrition and HealthImmune Response and Inflammation

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Lactoferrin in Aseptic and Septic Inflammation

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Lepanto, Maria Stefania, Rosa, Luigi, Paesano, Rosalba, Valenti, Piera, Cutone, Antimo·2019·Molecules
DOI 10.3390/molecules24071323PMC PMC6480387
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Abstract

Lactoferrin (Lf), a cationic glycoprotein able to chelate two ferric irons per molecule, is synthesized by exocrine glands and neutrophils. Since the first anti-microbial function attributed to Lf, several activities have been discovered, including the relevant anti-inflammatory one, especially associated to the down-regulation of pro-inflammatory cytokines, as IL-6. As high levels of IL-6 are involved in iron homeostasis disorders, Lf is emerging as a potent regulator of iron and inflammatory homeostasis. Here, the role of Lf against aseptic and septic inflammation has been reviewed. In particular, in the context of aseptic inflammation, as anemia of inflammation, preterm delivery, Alzheimer’s disease and type 2 diabetes, Lf administration reduces local and/or systemic inflammation. Moreover, Lf oral administration, by decreasing serum IL-6, reverts iron homeostasis disorders. Regarding septic inflammation occurring in Chlamydia trachomatis infection, cystic fibrosis and inflammatory bowel disease, Lf, besides the anti-inflammatory activity, exerts a significant activity against bacterial adhesion, invasion and colonization. Lastly, a critical analysis of literature in vitro data reporting contradictory results on the Lf role in inflammatory processes, ranging from pro- to anti-inflammatory activity, highlighted that they depend on cell models, cell metabolic status, stimulatory or infecting agents as well as on Lf iron saturation degree, integrity and purity.

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Crossref · 10.3390/molecules24071323

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Figure 1 Iron homeostasis in LPS-inflamed macrophages, in the absence (A) or presence (B) of lactoferrin. (A) LPS stimulation, triggered by LPS-binding protein (LBP) and CD-14, induces the nuclear translocation of cytoplasmic NF-κB which in turn induces IL-6 synthesis. Serum IL-6 down-regulates Fpn/Cp axis, inhibiting iron export from the macrophage to blood circulation. Consequently, the increase of intracellular iron pool (IP) triggers the up-regulation of intracellular Ftn and the down-regulation of TfR1 expression thus hindering additional intracellular iron accumulation. (B) Lf-mediated inflammatory-to-tolerogenic macrophagic shift. Lf is internalized by ITLN1-mediated endocytosis and translocated into the nucleus where it inhibits IL-6 synthesis. As a cascade, the inhibition of IL-6 synthesis restores Fpn/Cp-mediated iron export from the macrophage to blood circulation. Consequently, the decrease of intracellular IP triggers either the inhibition of Ftn synthesis and the up-regulation of TfR1, thus restoring the physiological iron balance between reticuloendothelial system and blood. LPS: lipopolysaccharide; LBP: LPS binding protein; NF-κB: nuclear factor-κB; IL-6: interleukin-6; IP: iron pool; Fpn: ferroportin; Cp: ceruloplasmin; Ftn: ferritin; Tf: transferrin; TfR1: transferrin receptor 1; Lf: lactoferrin; ITNL1: intelectin-1; STEAP3: six-transmembrane epithelial antigen of the prostate 3; DMT1: divalent metal transporter 1.
Figure 1 Iron homeostasis in LPS-inflamed macrophages, in the absence (A) or presence (B) of lactoferrin. (A) LPS stimulation, triggered by LPS-binding protein (LBP) and CD-14, induces the nuclear translocation of cytoplasmic NF-κB which in turn induces IL-6 synthesis. Serum IL-6 down-regulates Fpn/Cp axis, inhibiting iron export from the macrophage to blood circulation. Consequently, the increase of intracellular iron pool (IP) triggers the up-regulation of intracellular Ftn and the down-regulation of TfR1 expression thus hindering additional intracellular iron accumulation. (B) Lf-mediated inflammatory-to-tolerogenic macrophagic shift. Lf is internalized by ITLN1-mediated endocytosis and translocated into the nucleus where it inhibits IL-6 synthesis. As a cascade, the inhibition of IL-6 synthesis restores Fpn/Cp-mediated iron export from the macrophage to blood circulation. Consequently, the decrease of intracellular IP triggers either the inhibition of Ftn synthesis and the up-regulation of TfR1, thus restoring the physiological iron balance between reticuloendothelial system and blood. LPS: lipopolysaccharide; LBP: LPS binding protein; NF-κB: nuclear factor-κB; IL-6: interleukin-6; IP: iron pool; Fpn: ferroportin; Cp: ceruloplasmin; Ftn: ferritin; Tf: transferrin; TfR1: transferrin receptor 1; Lf: lactoferrin; ITNL1: intelectin-1; STEAP3: six-transmembrane epithelial antigen of the prostate 3; DMT1: divalent metal transporter 1.CC BY · PubMed Central
Figure 2 Schematic representation of the lactoferrin anti-inflammatory effects in different aseptic (red arrows) or septic (blue arrows) inflammatory pathologies. Lower and upper arrows indicate parameters decreased or increased, respectively.
Figure 2 Schematic representation of the lactoferrin anti-inflammatory effects in different aseptic (red arrows) or septic (blue arrows) inflammatory pathologies. Lower and upper arrows indicate parameters decreased or increased, respectively.CC BY · PubMed Central

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  1. Hainer, 2011, Vaginitis: Diagnosis and Treatment, Am. Fam. Physician., 83, 807

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Metadata

Authors
Lepanto, M. S., Rosa, L., Paesano, R., Valenti, P., & Cutone, A.
Affiliations
  • Sapienza University of Rome (IT)
  • Microbo S.R.L., 00153 Rome, Italy
  • University of Molise (IT)
Corresponding author
Cutone, Antimo
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2019-04-03
Volume
24
Issue
7
Pages
1323
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules24071323
PMC
PMC6480387
OpenAlex
W2935579023
Cited by
147
References
240
Citations by year
2026: 6 · 2025: 17 · 2024: 16 · 2023: 23 · 2022: 31 · 2021: 24 · 2020: 23 · 2019: 6
FWCI
3.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
Funders
Sapienza Università di Roma
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Nursing › Nutrition and Dietetics › Infant Nutrition and Health
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
lactoferrin, sterile inflammation, septic inflammation, interleukin-6, iron homeostasis, anti-inflammatory activity, anemia of chronic disease, preterm birth, Alzheimer's disease, type 2 diabetes, Chlamydia trachomatis infection, cystic fibrosis, inflammatory bowel disease, bacterial adhesion, iron saturation
MeSH terms
Anemia, Animals, Anti-Infective Agents, Anti-Inflammatory Agents, Humans, Inflammation, Iron, Lactoferrin, Biomarkers, Sepsis

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