Overview of Lactoferrin as a Natural Immune Modulator

Abstract

Lactoferrin is thought to be the most polyvalent protein present in host defense against tissue injuries and infections in vertebrates. Owing to the propensity of its basic N-terminal domain to interact with various microbial and host targets, lactoferrin not only has antimicrobial properties, but also modulates the innate and adaptive immune responses. Lactoferrin may indeed up- and downregulate immune cell activation, migration, and growth. Whereas the immunomodulatory properties of lactoferrin are evidenced from in vivo studies using either lactoferrin-knockout, lactoferrin-overexpressing transgenic models, and dietary lactoferrin, few mechanisms from in vitro studies have been proposed to explain these properties. The best characterized lactoferrin targets are negatively charged molecules. They encompass pro-inflammatory microbial molecules, such as pathogen-associated molecular patterns (eg, lipopolysaccharide), but also host components such as DNA, the glycosaminoglycan chains of proteoglycans, and surface cell receptors. Signaling through these receptors is thought to be the main lever used by lactoferrin to influence immune cells and cytokine-balance-controlling cell activity. This article aims to review our current understanding, though incomplete, of the many ways lactoferrin influences the complex immune machinery and the known and putative mechanisms that may explain its properties.

Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections

“…Although Lf displays direct microbiostatic and/or microbicidal activities, indirect antimicrobial mechanisms have also been ascribed to its capability of modulating a wide array of humoral and cellular components of the innate and adaptive immunity [3,94]. Immunomodulatory role of Lf is due, in part, to its interactions with cell surface receptors that favor either elicitation of signal pathways, or Lf translocation into nucleus and gene targeting [95,96,97].…”

“…Lf is also able to up- and down-modulate both humoral and cellular components of immunity involved in the regulation of the inflammatory response having a key role in maintaining gut homeostasis [3]. Balance of homeostasis results from the tight regulation of several events, since too little inflammation disrupts the process of tissue repairing and remodeling, whereas too much inflammation entails collateral impact by causing tissue damage with life-threatening consequences [128].…”

“…Antimicrobial activity has been mostly characterized in Lf of bovine and human origin isolated from milk [2,3]. Mechanisms underlying the antimicrobial action of Lf result from both direct (microbiostatic and/or microbicidal) and indirect (immunomodulatory) effects [3,4,5].…”

“…Antimicrobial activity has been mostly characterized in Lf of bovine and human origin isolated from milk [2,3]. Mechanisms underlying the antimicrobial action of Lf result from both direct (microbiostatic and/or microbicidal) and indirect (immunomodulatory) effects [3,4,5]. At present, the therapeutic and prophylactic treatments for microbial infections that ameliorate both the antibiotic multiresistance and the inflammatory response have prompted the searching of agents that display both antimicrobial and modulatory properties such as Lf.…”

Neutrophils and Immunity: From Bactericidal Action to Being Conquered

“…These proteins are very potent and specific inhibitors of NSPs and imply a crucial role for NSPs in the defense against S. aureus . Iron-regulated surface determinant protein H (IsdH) is present in the surface of S. aureus , which binds to lactoferrin, the most abundant antistaphylococcal polypeptide [121]. IsdA confers resistance to killing by lactoferrin.…”