Human lactoferrin attenuates the proinflammatory response of neonatal monocyte-derived macrophages

Abstract

SummaryBioactive components of human milk, such as human lactoferrin (hLF), play an essential role in gut microbiome homeostasis and protection against neonatal inflammatory diseases. Neonatal intestinal macrophages display a proinflammatory profile that might contribute to inflammatory mucosal injury. Therefore, the aim of the study was to investigate the immunomodulatory effects of hLF on differentiation and activation of monocyte‐derived macrophages (moMϕ). Monocytes isolated from umbilical cord blood of term neonates and peripheral blood of healthy adults were differentiated in the absence or presence of hLF, and differentiation, apoptosis and phagocytosis were evaluated. Cytokine production, Toll‐like receptor (TLR) signalling and activation marker expression were investigated upon activation with lipopolysaccharide (LPS) and lipoteichoic acid (LTA) challenge. We demonstrate that hLF‐differentiated moMϕ exhibit decreased TLR‐4 expression, TLR signalling, proinflammatory cytokine secretion and intracellular tumour necrosis factor (TNF)‐α production. Investigation of differentiation markers, morphology and induction of apoptosis showed no alteration in lactoferrin‐differentiated moMϕ. Taken together, hLF promote anergic/anti‐inflammatory effects by TLR expression and pathway interference, resulting in a diminished proinflammatory moMϕ phenotype. The anergic/anti‐inflammatory properties of hLF might contribute to the prevention of harmful TLR‐mediated inflammatory disorders in the developing gut of premature infants.

Distribution of Lactoferrin Is Related with Dynamics of Neutrophils in Bacterial Infected Mice Intestine

“…E. coli K88 infection promoted the gene expression of Lf in the duodenum, ileum and colon. We supposed that the increased expression of Lf might be correlated with its function of anti-inflammatory, which is in line with previous report that Lf attenuated the pro-inflammatory response of monocyte-derived macrophages via interaction of the TLR4-specific pathway [17]. Multiple biological activities of Lf depend on its target cells and on the presence of LfR at their surfaces.…”

Lactoferrin (LF): a natural antimicrobial protein

“…Infant formulas enriched with 1 mg/ml promoted beneficial microflora comprising bifidobacteria and reduced clostridium in the gut in low weight as a well normal newborn. [81] Wisgrill, Wessely, Spittler, Förster-Waldl, Berger and Sadeghi [82] opined that LF killed E-coli in the gut of adolescents. Bovine Lf is also exhibited to clear an E-coli infection in cattle.…”

Immunomodulation to Prevent or Treat Neonatal Sepsis: Past, Present, and Future

“…(B) The microbiome of premature infants has a smaller proportion of beneficial bacteria and higher numbers of pathogenic bacteria compared to term infants, likely owing to higher frequencies of cesarean sections, antibiotic use, exposure to the hospital environment, and artificial feeding ( 130 ). The administration of probiotics up-regulates local and systemic immunity by (1) decreasing proinflammatory cytokines, (2) increasing the production of anti-inflammatory cytokines, and (3) decreasing the permeability of the gut to bacteria and toxins ( 131 ). (C) Human milk contains a range of distinct bioactive molecules that protect against infection and inflammation including immunoglobulins, long-chain PUFAs, and LF.…”

“…Lactoferrin directly interacts with TLR4 and CD14 and demonstrates bacteriostatic activity through its high affinity for iron its ability to directly bind LPS ( 163 , 164 ). In addition to its function as an antimicrobial protein, lactoferrin has also demonstrated immunoregulatory properties in vitro and in vivo ( 131 , 165 , 166 ). These studies indicate a potential role of lactoferrin as an immune-sensor to maintain immune homeostasis with an immunosuppressive effect on inflammatory monocytes/macrophages of preterm neonates ( 30 , 131 , 167 ).…”