The Functional Role of Lactoferrin in Intestine Mucosal Immune System and Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is one of the main types of intestinal inflammatory diseases with intestine mucosal immune disorder. Intestine mucosal immune system plays a remarkable and important role in the etiology and pathogenesis of IBD. Therefore, understanding the intestine mucosal immune mechanism is a key step to develop therapeutic interventions for IBD. Intestine mucosal immune system and IBD are influenced by various factors, such as inflammation, gut permeability, gut microbiota, and nutrients. Among these factors, emerging evidence show that nutrients play a key role in inflammation activation, integrity of intestinal barrier, and immune cell modulation. Lactoferrin (LF), an iron-binding glycoprotein belonging to transferrin family, is a dietary bioactive component abundantly found in mammalian milk. Notably, LF has been reported to perform diverse biological functions including antibacterial activity, anti-inflammatory activity, intestinal barrier protection, and immune cell modulation, and is involved in maintaining intestine mucosal immune homeostasis. The improved understanding of the properties of LF in intestine mucosal immune system and IBD will facilitate its application in nutrition, clinical medicine, and health. Herein, this review outlines the recent advancements on LF as a potential therapeutic intervention for IBD associated with intestine mucosal immune system dysfunction. We hope this review will provide a reference for future studies and lay a theoretical foundation for LF-based therapeutic interventions for IBD by understanding the particular effects of LF on intestine mucosal immune system.

Keywords: cytokine; immunocytes; inflammatory bowel disease; intestinal epithelial cells; intestine mucosal immune system; lactoferrin.

Figure 1

Intestine mucosal immune system landscape. The intestine mucosal immune system is composed of different types of functional cells. Enterocytes, the main functional cells of intestine mucosal immune, are responsible for the absorption of nutrients and water, and also produce antimicrobial peptides (such as RegIIIγ and β-defensin). Paneth cells located at the bottom of the crypt produce amounts of specific antimicrobial peptides (α-defensin). M cells function to sample and transport antigens to immune cells. Goblet cells secrete mucins and promote luminal antigen transfer to DCs. In addition, there are a large number of immune cells distributed in the intestinal epithelium and LP, including DCs, B cells, and T cells. DCs are specialized antigen-presenting cells. After antigens stimulation, they secrete cytokine IFN-γ, which further stimulates monocyte macrophages to secrete IL-10. The DCs that migrate to the MLNs promote the differentiation and maturation of initial T cells. These differentiated and mature T cells can secrete immune factors to participate in intestine mucosal immune system. DCs, dendritic cells; IFN-γ, interferon-γ; IL-10, interleukin-10; LP, lamina propria; M, microfold; MLNs, mesenteric lymph nodes; RegIIIγ, regenerating islet-derived protein IIIγ.

Figure 2

The functional role of LF on intestine mucosal immune system in the context of IBD. Without LF (Left), the intestine mucosal immune system follows the path of autoimmune regulation. The presence of LF (Right) promotes TJ between epithelial cells, enhances the expression of β-catenin, and activates the Wnt signaling pathway. LF downregulates the protein abundance of MLCK, reduces the level of ROS and MDA, enhances GSH-Px activity, and upregulates the expression level of Nrf2 in epithelial cells. LF enhances the expression level of TLRs and activates the NF-κB pathway. LF also reduces the secretion and the gene expression of IL-1β, enhances the function of immune cells, promotes the production of cytokines, and promotes the recruitment of immune cells. GSH-Px, glutathione peroxidase; IL-1β, interleukin-1β; LF, lactoferrin; NF-κB, nuclear factor kappa-B; Nrf2, nuclear factor erythroid 2-related factor 2; MDA, malondialdehyde; MLCK, myosin light chain kinase; ROS, reactive oxygen species; TJ, tight junction; TLRs, toll-like receptors.