Elafin and its precursor trappin-2: What is their therapeutic potential for intestinal diseases?

Abstract

Elafin and its precursor trappin-2 are known for their contribution to the physiological mucosal shield against luminal microbes. Such a contribution seems to be particularly relevant in the gut, where the exposure of host tissues to heavy loads of microbes is constant and contributes to mucosa-associated pathologies. The expression of trappin-2/elafin has been shown to be differentially regulated in diseases associated with gut inflammation. Accumulating evidence has demonstrated the protective effects of trappin-2/elafin in gut intestinal disorders associated with acute or chronic inflammation, or with gluten sensitization disorders. The protective effects of trappin-2/elafin in the gut are discussed in terms of their pleiotropic modes of action: acting as protease inhibitors, transglutaminase substrates, antimicrobial peptides or as a regulator of pro-inflammatory transcription factors. Further, the question of the therapeutic potential of trappin-2/elafin delivery at the intestinal mucosa surface is raised. Whether trappin-2/elafin mucosal delivery should be considered to ensure intestinal tissue repair is also discussed.

Keywords: colitis; elafin; inflammation; inflammatory bowel disease; protease; trappin.

FIGURE 1

Diagram of trappin‐2 and elafin with location of their biological functions. The elafin domain (WAP domain) is released from trappin‐2 (containing both cementoin and WAP domains) after proteolytic cleavage at amino acid 38. The cementoin domain has a α‐helix structure (blue ribbon), and the WAP domain contains the anti‐protease activity (pink triangle). Associated biological functions are shown on the left for the cementoin domain and on the right for the WAP domain. Blue hexagons with T sign correspond to the repeated motifs rich in Gln and Lys residues, substrate of transglutaminase. Amino acids numbers are in grey and italics.

FIGURE 2

Pleiotropic mechanisms of action of trappin‐2/elafin. The anti‐protease WAP domain (pink triangle) is important to control proteolytic activity and interferes with NF‐kB/AP‐1 pathways. Trappin‐2/elafin has demonstrated anti‐microbial properties against bacteria but also potentially against some fungi, viruses and parasites. Trappin‐2/elafin contains substrate motifs for transglutaminase.

FIGURE 3

Constitutive expression of elafin along the digestive tract and cellular origin. In colonic tissues, elafin is constitutively expressed by epithelial cells and γδ T‐lymphocytes. During inflammation, infiltrated immune cells such as macrophages and neutrophils also constitute a source of elafin. The schematic representation of mRNA expression level of the PI3 gene encoding trappin‐2/elafin, in different parts of the gastrointestinal tract in physiological conditions has been extracted from the human protein atlas website (https://www.proteinatlas.org/ENSG00000124102‐PI3/tissue). nTPM, normalized protein‐coding transcripts per million

FIGURE 4

Potential effects of trappin‐2/elafin delivery on mucosal dysfunction, associated with intestinal inflammation. Experimentally demonstrated, inferred or hypothetical roles are shown.