Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally-occurring peptides which can combat infections through their direct microbicidal properties and/or by influencing the host's immune responses. The unique ability of CHDP to control infections as well as resolve harmful inflammation has generated interest in harnessing the properties of these peptides to develop new therapies for infectious diseases, chronic inflammatory disorders and wound healing. Various strategies have been employed to design synthetic optimized peptides, with negligible toxicity. Here, we focus on the progress made in understanding the scope of functions of CHDP and the emerging potential clinical applications of CHDP-based therapies. This has led to the adoption of the current name for this family of peptides, Cationic Host Defence Peptides, which encompasses the wide range of described functions. Over the last three decades there has been substantial interest in therapeutically harnessing CHDP, with more than 5000 papers published in this area of research since 2017 alone. These include the examination of potential clinical uses for CHDP ranging from infections including multidrug-resistant bacteria 16-19 , to chronic inflammatory diseases such as arthritis 20 , asthma 21 and colitis 22 , as well as some cancers 23. Peptide-based therapeutics currently in clinical trials are primarily for the treatment of infections such as respiratory, oral and catheter-related infections, and for wound healing (see http://dramp.cpu-bioinfor.org/browse/ClinicalTrialsData.php). This review will provide an overview of current understanding of the scope of functions of CHDP, primarily from eukaryotes. Emerging therapeutic applications of these peptides, current clinical trials and the associated clinical developmental challenges will be discussed. Although there is increasing interest in the development of non-peptide mimics of CHDP for therapeutic application, such as peptoid analogs (reviewed in 24), a comprehensive discussion of these approaches is beyond the scope of this review. [H1] Naturally occurring CHDP The antimicrobial peptide database has catalogued more than 2600 natural antimicrobial peptides, including those annotated as immunomodulatory 25. The major families of CHDP from eukaryotes that are of interest from a drug discovery perspective are summarized below. [H2] Vertebrate CHDP CHDP from vertebrates have an essential role in the first line of defense against microbial pathogens. Upon infection, CHDP can kill pathogens through diverse mechanisms 26-31 (discussed below), acting rapidly and directly on the pathogen when present in high local concentrations, or indirectly to modify components of host defense. These peptides exhibit immunomodulatory activities that can be either pro-or anti-inflammatory depending on the phase of the infection (see below) 12-14,29. CHDP from vertebrates are amphipathic peptides containing amino acids with hydrophilic and hydrophobic side chains at opposite sides of the molec...
The sole human cathelicidin peptide, LL-37, has been demonstrated to protect animals against endotoxemia/sepsis. Low, physiological concentrations of LL-37 (≤1 μg/ml) were able to modulate inflammatory responses by inhibiting the release of the proinflammatory cytokine TNF-α in LPS-stimulated human monocytic cells. Microarray studies established a temporal transcriptional profile and identified differentially expressed genes in LPS-stimulated monocytes in the presence or absence of LL-37. LL-37 significantly inhibited the expression of specific proinflammatory genes up-regulated by NF-κB in the presence of LPS, including NFκB1 (p105/p50) and TNF-α-induced protein 2 (TNFAIP2). In contrast, LL-37 did not significantly inhibit LPS-induced genes that antagonize inflammation, such as TNF-α-induced protein 3 (TNFAIP3) and the NF-κB inhibitor, NFκBIA, or certain chemokine genes that are classically considered proinflammatory. Nuclear translocation, in LPS-treated cells, of the NF-κB subunits p50 and p65 was reduced ≥50% in the presence of LL-37, demonstrating that the peptide altered gene expression in part by acting directly on the TLR-to-NF-κB pathway. LL-37 almost completely prevented the release of TNF-α and other cytokines by human PBMC following stimulation with LPS and other TLR2/4 and TLR9 agonists, but not with cytokines TNF-α or IL-1β. Biochemical and inhibitor studies were consistent with a model whereby LL-37 modulated the inflammatory response to LPS/endotoxin and other agonists of TLR by a complex mechanism involving multiple points of intervention. We propose that the natural human host defense peptide LL-37 plays roles in the delicate balancing of inflammatory responses in homeostasis as well as in combating sepsis induced by certain TLR agonists.
We show that an innate defense-regulator peptide (IDR-1) was protective in mouse models of infection with important Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and Salmonella enterica serovar Typhimurium. When given from 48 h before to 6 h after infection, the peptide was effective by both local and systemic administration. Because protection by IDR-1 was prevented by in vivo depletion of monocytes and macrophages, but not neutrophils or B- and T-lymphocytes, we conclude that monocytes and macrophages are key effector cells. IDR-1 was not directly antimicrobial: gene and protein expression analysis in human and mouse monocytes and macrophages indicated that IDR-1, acting through mitogen-activated protein kinase and other signaling pathways, enhanced the levels of monocyte chemokines while reducing pro-inflammatory cytokine responses. To our knowledge, an innate defense regulator that counters infection by selective modulation of innate immunity without obvious toxicities has not been reported previously.
An increase in antibiotic resistance and the emergence of new pathogens has led to an urgent need for alternative approaches to infection management. Immunomodulatory molecules that do not target the pathogen directly, but rather selectively enhance and/or alter host defence mechanisms, are attractive candidates for therapeutic development. Natural cationic host defence peptides represent lead molecules that boost innate immune responses and selectively modulate pathogen-induced inflammatory responses. This review discusses recent evidence exploring the mechanisms of cationic host defence peptides as innate immune regulators, their role in the interface of innate and adaptive immunity, and their potential application as beneficial therapeutics in overcoming infectious diseases.
Host defence peptides (HDPs) are innate immune effector molecules found in diverse species. HDPs exhibit a wide range of functions ranging from direct antimicrobial properties to immunomodulatory effects. Research in the last decade has demonstrated that HDPs are critical effectors of both innate and adaptive immunity. Various studies have hypothesized that the antimicrobial property of certain HDPs may be largely due to their immunomodulatory functions. Mechanistic studies revealed that the role of HDPs in immunity is very complex and involves various receptors, signalling pathways and transcription factors. This review will focus on the multiple functions of HDPs in immunity and inflammation, with special reference to cathelicidins, e.g. LL-37, certain defensins and novel synthetic innate defence regulator peptides. We also discuss emerging concepts of specific HDPs in immune-mediated inflammatory diseases, including the potential use of cationic peptides as therapeutics for immune-mediated inflammatory disorders.
The human cathelicidin LL-37 is a cationic host defense peptide and serves as an important component of innate immunity. It has been demonstrated to be a multifunctional modulator of innate immune responses, although the mechanism(s) underlying this have not been well characterized. In this study, it was demonstrated that LL-37 synergistically enhanced the IL-1β-induced production of cytokines (IL-6, IL-10) and chemokines such as macrophage chemoattractant proteins (MCP-1, MCP-3) in human PBMC, indicating a role in enhancing certain innate immune responses. Similarly, LL-37 synergistically enhanced chemokine production in the presence of GM-CSF, but IFN-γ, IL-4, or IL-12 addition led to antagonism, indicating that the role of LL-37 in reinforcing specific immune responses is selective and restricted to particular endogenous immune mediators. The inhibition of G protein-coupled receptors and PI3K substantially suppressed the ability of IL-1β and LL-37 to synergistically enhance the production of chemokine MCP-3. Consistent with this, the combination of IL-1β and LL-37 enhanced the activation/phosphorylation of kinase Akt and the transcription factor CREB. The role of transcription factor NF-κB was revealed through the demonstration of enhanced phosphorylation of IκBα and the consequent nuclear translocation of NF-κB subunits p50 and p65, as well as the antagonistic effects of an inhibitor of IκBα phosphorylation. These results together indicate that the human host defense peptide LL-37 can work in synergy with the endogenous inflammatory mediator IL-1β to enhance the induction of specific inflammatory effectors by a complex mechanism involving multiple pathways, thus reinforcing certain innate immune responses.
The human cationic host defense peptide LL-37 has a broad range of immunomodulatory, anti-infective functions. A synthetic innate defense regulator peptide, innate defense regulator 1 (IDR-1), based conceptually on LL-37, was recently shown to selectively modulate innate immunity to protect against a wide range of bacterial infections. Using advanced proteomic techniques, ELISA, and Western blotting procedures, GAPDH was identified as a direct binding partner for LL-37 in monocytes. Enzyme kinetics and mobility shift studies also indicated LL-37 and IDR-1 binding to GAPDH. The functional relevance of GAPDH in peptide-induced responses was demonstrated by using gene silencing of GAPDH with small interfering RNA (siRNA). Previous studies have established that the induction of chemokines and the anti-inflammatory cytokine IL-10 are critical immunomodulatory functions in the anti-infective properties of LL-37 and IDR-1, and these functions are modulated by the MAPK p38 pathway. Consistent with that, this study demonstrated the importance of the GAPDH interactions with these peptides since gene silencing of GAPDH resulted in impaired p38 MAPK signaling, downstream chemokine and cytokine transcriptional responses induced by LL-37 and IDR-1, and LL-37-induced cytokine production. Bioinformatic analysis, using InnateDB, of the major interacting partners of GAPDH indicated the likelihood that this protein can impact on innate immune pathways including p38 MAPK. Thus, this study has demonstrated a novel function for GAPDH as a mononuclear cell receptor for human cathelicidin LL-37 and immunomodulatory IDR-1 and conclusively demonstrated its relevance in the functioning of cationic host defense peptides.
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