Expression and Function of Host Defense Peptides at Inflammation Sites

Abstract

There is a growing interest in the complex role of host defense peptides (HDPs) in the pathophysiology of several immune-mediated inflammatory diseases. The physicochemical properties and selective interaction of HDPs with various receptors define their immunomodulatory effects. However, it is quite challenging to understand their function because some HDPs play opposing pro-inflammatory and anti-inflammatory roles, depending on their expression level within the site of inflammation. While it is known that HDPs maintain constitutive host protection against invading microorganisms, the inducible nature of HDPs in various cells and tissues is an important aspect of the molecular events of inflammation. This review outlines the biological functions and emerging roles of HDPs in different inflammatory conditions. We further discuss the current data on the clinical relevance of impaired HDPs expression in inflammation and selected diseases.

Keywords: anti-inflammatory; cathelicidins; defensins; host defense peptides; human antimicrobial peptides; inflammation; pro-inflammatory.

Figure 1

Illustration of the distinct role of host defense peptides at the sites of inflammation. Specific Toll-like receptors TLR-2, TLR-4, TLR-5, and TLR-6 are expressed on the plasma membrane of immune cells, non-immune cells, and intracellular compartments. TLR-7 and TLR-9 within endosomes participate in the host recognition of microbial cellular components and bind to host internal factors. The receptors, along with their adaptor proteins MyD88 and TRIF, can initiate the inflammatory signaling pathways. The host defense peptides promote innate immunity against various pathogens and maintain the immune system homeostasis. These peptides can also be induced in addition to their constitutive expression by the transcriptional modulatory factors NF-κB, AP-1, and intracellular release of cytokines and chemokines. They actively participate in coordinating the host immune signaling mechanisms during inflammation. Furthermore, HDPs can display both pro- and anti-inflammatory properties that may protect against the responses of inflammatory diseases. Abbreviations: AP-1, activator protein; NF-kB, nuclear factor kappa-light-chain enhancer of activated B cells; MAPK, mitogen-activated protein kinase; ERK1,2, extracellular signal-related kinases.

Figure 2

Comparison of human host defense peptides (n = 133) curated in antimicrobial peptide database (http://aps.unmc.edu/AP; accessed in September 2019). The dendrogram was built based on amino acid sequence alignment using MAFFT aligner (https://mafft.cbrc.jp) [65], visualized and annotated with Archaeopteryx [66] and iTOL [67], respectively. Net charge values of the peptides (at pH = 7.0) were estimated using Protein Calculator https://pepcalc.com/protein-calculator.php [68].

Figure 3

Network of interactions between α-defensin 1 gene (DEFA-1) and other human proteins (the network was obtained from STRING v11 database) [87]. Represented proteins are central to antimicrobial and immunomodulatory activities. Abbreviations: AGER, advanced glycosylation end-product-specific receptor; BPI, bactericidal permeability increasing protein; CAMP, cathelicidin antimicrobial peptide; CLU, clusterin; CTSG, cathepsin; DEFA3, defensin alpha 3; DEFA4, defensin alpha 4; DEFA5, defensin alpha 5; DEFA1B, defensin alpha 1B; DEFB4A, defensin beta 4A; DEFB1, defensin beta 1; DEFB132, defensin beta 132; DEFB127, defensin beta 127; ELANE, neutrophil elastase; GRN, granulin precursor; LCN2, lipocalin 2; LTF, lactotransferrin; LYZ, lysozyme; MPO, myeloperoxidase; MMP8, matrix metallopeptidase 8; ORC1, origin recognition complex subunit 1; PGLYRP1, peptidoglycan recognition protein 1; PRTN3, proteinase 3; RNASE3, ribonuclease A family member 3; SLP I, secretory leukocyte peptidase inhibitor; S100A8, S100 calcium binding protein A8; S100A9, S100 calcium binding protein A9; S100A12, S100 calcium binding protein A12; TCN1, transcobalamin 1.

Figure 4

Relative expression of selected host defense peptide (HDP) genes in the human skin, based on RNA-seq analysis of tissue samples from 95 human individuals performed by Fagerberg et al. [107]. The data were obtained from the GenBank Bio Project: PRJEB4337 (RPKM, reads per kilobase per million reads).