Abstract
Host-defense peptides (HDPs) have an important therapeutic potential against microbial infections but their metabolic instability and cellular cytotoxicity have limited their utility. To overcome these limitations, we utilized five small-molecule, nonpeptide HDP mimetics (smHDPMs) and tested their effects on cytotoxicity, antimicrobial activity, and mast cell (MC) degranulation. None of the smHDPMs displayed cytotoxicity against mouse 3T3 fibroblasts or human transformed liver HepG2 cells. However, one compound had both antifungal and antibacterial activity. Surprisingly, all five compounds induced degranulation in a human MC line, LAD2, and this response was substantially reduced in Mas-related G protein-coupled receptor (GPCR)-X2 (MRGPRX2)-silenced cells. Furthermore, all five compounds induced degranulation in RBL-2H3 cells expressing MRGPRX2 but this response was abolished in cells expressing naturally occurring loss-of-function missense variants G165E (rs141744602) and D184H (rs372988289). Mrgprb2 is the likely mouse ortholog of human MRGPRX2, which is expressed in connective tissue MCs (CTMCs) such as cutaneous and peritoneal MCs (PMCs). All five smHDPMs induced degranulation in wild-type PMCs but not in cells derived from Mrgprb2−/− mice. These findings suggest that smHDPMs could serve as novel targets for the treatment of drug-resistant fungal and bacterial infections because of their ability to harness CTMCs’ host defense functions.
Highlights
Mast cells (MCs) are granulated immune cells of hematopoietic origin that are widely distributed in tissues such as the skin and mucosal tissues that interact with the environment
A series synthetic synthetic compounds based on a meta-phenylene backbone has been synthesized and tested for compounds based on a meta-phenylene backbone has been synthesized and tested for antimicrobial antimicrobial activity
Bone-marrow-derived mast cells (BMMCs), which do not express Mrgprb2 [8], did not respond to compound 48/80 or any of the small-molecule HDP mimetics (smHDPMs) tested despite their normal responsiveness to antigen/IgE for degranulation (Figure 6D). These findings demonstrate that all five smHDPMs used in this study induce degranulation in mouse connective tissue MCs (CTMCs) via the activation of Mrgprb2
Summary
Mast cells (MCs) are granulated immune cells of hematopoietic origin that are widely distributed in tissues such as the skin and mucosal tissues that interact with the environment. MCs are best known for their roles in IgE-mediated allergic reactions, their most important functions likely include tissue homeostasis, host defense, and wound healing [1,2,3,4]. Skin MCs are known as MCTC because their secretory granules contain both tryptase and chymase but those present in the lung are known as MCT because their secretory granules contain only tryptase [5]. Skin MCs resemble human MCTC and are referred to as connective tissue MCs (CTMCs) but lung MCs resemble human MCT and are known as mucosal MCs (MMCs). CTCMs contain abundant heparin in their granules but MMCs do not
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