Intestinal antimicrobial peptides during homeostasis, infection, and disease

Abstract

Antimicrobial peptides (AMPs), including defensins and cathelicidins, constitute an arsenal of innate regulators of paramount importance in the gut. The intestinal epithelium is exposed to myriad of enteric pathogens and these endogenous peptides are essential to fend off microbes and protect against infections. It is becoming increasingly evident that AMPs shape the composition of the commensal microbiota and help maintain intestinal homeostasis. They contribute to innate immunity, hence playing important functions in health and disease. AMP expression is tightly controlled by the engagement of pattern recognition receptors (PRRs) and their impairment is linked to abnormal host responses to infection and inflammatory bowel diseases (IBD). In this review, we provide an overview of the mucosal immune barriers and the intricate crosstalk between the host and the microbiota during homeostasis. We focus on the AMPs and pay particular attention to how PRRs promote their secretion in the intestine. Furthermore, we discuss their production and main functions in three different scenarios, at steady state, throughout infection with enteric pathogens and IBD.

Keywords: NOD-like receptors; Toll-like receptors; antimicrobial peptides; enteric pathogens; homeostasis; inflammatory bowel disease; innate immunity; intestine.

FIGURE 1

Intestinal mucosal surface at the steady state. The intestinal epithelial barrier is a highly organized mucosal surface that prevents the entry of microbes into the lamina propria. The epithelium is constituted of a single layer of intestinal epithelial cells (IECs) covered by a stratified mucus layer. Unlike the outer mucus layer that is colonized by commensal species, the inner mucus layer is mostly devoid of bacteria; it contains Immunoglobulin A (IgA) and antimicrobial peptides (AMPs) that avert the commensal species from interacting with the surface of the IECs. Yet, few opportunistic bacteria such as segmented filamentous bacteria (SFB) can breach the mucus barrier and enter in contact with the IECs. There are five IEC lineages derived from epithelial stem cells that proliferate and give rise to daughter cells. These cells include enterocytes, mucus-producing goblet cells, hormone-producing enteroendocrine cells, AMP-producing Paneth cells at the base of the crypts and finally, M cells that sample antigens from the intestinal lumen in order to present them to nearby immune cells. A high number of T cells, macrophages, IgA secreting B and plasma cells are present in the lamina propria and the Peyer’s patches. In addition, CD103⁺CD11b^- and CD103⁺CD11b⁺ dendritic cells (DCs) promote the development of T helper (Th17) and T regulatory (Treg) cells respectively, while CX₃CR1⁺ DCs sample the lumen antigenic content.

FIGURE 2

Regulation of AMP secretion by TLRs and NLRs during homeostasis and infection. AMPs, mainly secreted by enterocytes and Paneth cells, are found in the inner mucus layer and play important roles in the barrier against enteric pathogens. At the steady state, microbial-associated molecular patterns, (MAMPs, green stars) from commensal bacteria are sensed by pattern recognition receptors (PRRs). They trigger basal AMP and interleukin-18 (IL-18) production through the activation of NF-κB and inflammasome pathways, respectively. This participates in the tuning of host responses toward tolerance and help maintaining intestinal homeostasis. Loss of homeostasis occurs when pathogens breach the mucus layer, enter in contact with IECs and disrupt the epithelial barrier integrity. Pathogens and their products (MAMPs, red stars) are also sensed by PRRs and induce MyD88- or inflammasome-dependent expression of a pro-inflammatory and antimicrobial program. In consequence, high levels of AMPs and cytokines/chemokines are produced that help limit pathogen propagation and contribute to the recruitment of immune cells. hBD, human β-defensin; mBD, mouse β-defensin; HD, human α-defensin.