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.
Highlights
Iron and InflammationIron is necessary for pivotal metabolic processes such as energy production, DNA synthesis/repair/transcription, oxygen transport/storage and drug detoxification
The efficacy of Human Lf (hLf), recombinant hLf (rhLf), bovine Lf (bLf) and commercial bLf (cbLf) in exerting their multiple functions can be critically influenced by purity, integrity, iron or other metal ions saturation rate, N-glycosylation and sialylation profiles and by their ability to enter inside the nucleus [36]
The relationship between humans and microbes is multifaceted: even if the vast majority of microorganisms are innocuous and beneficial to the host, some microorganisms can shift towards a pathogenic phenotype, defined as pathobiont [156,159], able to adhere to the host, invade underlying tissues and multiply evading host immune defenses [160]
Summary
Iron is necessary for pivotal metabolic processes such as energy production, DNA synthesis/repair/transcription, oxygen transport/storage and drug detoxification. ROS formation, causative of damages to lipids, nucleic acids and proteins, is involved in the cell, tissue and organ oxidative stress and injury with consequent activation of either acute or chronic inflammatory processes implicated in multiple degenerative clinical conditions including the development of cancer, obesity, diabetes and aging. High hepcidin levels, hindering iron export by Fpn, lead to intracellular iron overload as well as to a decrease of the iron import systems as Dcytb, DMT1 and TfR1 [15]. Several connections among immune cells, primary and secondary mediators defend host against systemic infections or pathological destructive inflammation supporting damaged tissue repair [25]. We’ll refer to infection-unrelated inflammation as “aseptic inflammation” and to infection-related inflammation as “septic inflammation”
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