Antimicrobial host defence peptides: functions and clinical potential

Cationic host defence peptides (CHDP), also known as antimicrobial peptides, are naturally occurring peptides that 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 used 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

Functions of Cationic Host Defense Peptides in Immunity

Cationic host defense peptides are a widely distributed family of immunomodulatory molecules with antimicrobial properties. The biological functions of these peptides include the ability to influence innate and adaptive immunity for efficient resolution of infections and simultaneous modulation of inflammatory responses. This unique dual bioactivity of controlling infections and inflammation has gained substantial attention in the last three decades and consequent interest in the development of these peptide mimics as immunomodulatory therapeutic candidates. In this review, we summarize the current literature on the wide range of functions of cationic host defense peptides in the context of the mammalian immune system

Ultrashort Cationic Lipopeptides and Lipopeptoids Selectively Induce Cytokine Production in Macrophages

<div><p>A series of ultrashort lipopeptides and lipopeptoids were tested for their ability to induce cytokine production in macrophages. Fourteen compounds were found to strongly induce production of chemokines Groα and IL-8, with a structural bias that was absent from previous antibacterial activity investigations. Compounds based on LysGlyLys and <em>N</em>LysGly<em>N</em>Lys sequences did not induce cytokine production, whereas those based on LysLysLys and <em>N</em>Lys<em>N</em>Lys<em>N</em>Lys were active only when linked to a lipid tail at least sixteen carbons long. Three lipopeptides induced high levels of IL-8 production, above that of equivalent concentrations of cathelicidin LL-37, while no compound induced production of the pro-inflammatory cytokine TNF-α at or below 100 µM. Two compounds, peptoids C16OH-<em>N</em>Lys<em>N</em>Lys<em>N</em>Lys and C16OH-<em>N</em>Har<em>N</em>Har<em>N</em>Har, were selective for IL-8 production and did not induce TNF-α or IL-1β. These compounds may prove beneficial for in vivo treatment of infectious disease, with improved bioavailability over LL-37 due to their protease-resistant scaffold.</p> </div

Structures for the cationic amphiphiles used in this study.

<p>Har = homoarginine; <i>N</i>Lys = lysine peptoid; <i>N</i>Har = homoarginine peptoid.</p

Cytokines IL-17, TNF and IFN-γ Alter the Expression of Antimicrobial Peptides and Proteins Disparately: A Targeted Proteomics Analysis using SOMAscan Technology

Antimicrobial peptides, also known as host defence peptides, are immunomodulatory molecules required to resolve infections. Antimicrobial peptides and proteins (APPs) are important in the control of infections in the lungs. Despite evidence that APPs exhibit a wide range of immune functions and modulate inflammation, the effect of inflammatory cytokines on the expression of APPs is not completely defined. In this study, we profiled the expression of 39 different APPs in human bronchial epithelial cells (HBEC) using Slow Off-rate Modified Aptamer (SOMAmer)-based protein array, in the presence and absence of three different inflammatory cytokines (IL-17, TNF and IFN-&gamma;). Expression of 13 different APPs was altered in response to IL-17, TNF or IFN-&gamma;. Independent validations of selected proteins from the proteomics screen i.e., those that were significantly enhanced by &gt;2-fold change (p &lt; 0.01) using western blots conclusively demonstrated that inflammatory cytokines alter the expression of APPs differentially. For example, the abundance of cathepsin S was enhanced by only IFN-&gamma;, whereas lipocalin-2 was increased by IL-17 alone. Abundance of elafin increased in presence of IL-17 or TNF, but decreased in response to IFN-&gamma;. Whereas the abundance of cathepsin V decreased following stimulation with IL-17, TNF and IFN-&gamma;. The results of this study demonstrate that inflammatory cytokines alter the expression of APPs disparately. This suggests that the composition of the inflammatory cytokine milieu may influence APPs abundance and thus alter the processes required for infection control and regulation of inflammation in the lungs

IL-1β production.

<p>Human macrophage-like THP-1 cells were exposed to amphiphiles <b>4–11</b> and <b>14–21</b>, for twenty-four hours. TC supernatants were monitored for IL-1β by ELISA, with results shown in pg/mL. Studies were performed in two independent biological replicates with two technical replicate each, with the data here presented as the mean plus sem. Inset: Expanded results for the negative control and amphiphiles <b>4–7</b> at 5 µM and 10 µM.</p

Circulating levels of free 25(OH)D increase at the onset of rheumatoid arthritis.

OBJECTIVE:Epidemiological studies suggest vitamin D deficiency as a potential risk factor for rheumatoid arthritis (RA) development, a chronic autoimmune disorder highly prevalent in indigenous North American (INA) population. We therefore profiled the circulating levels of 25-hydroxyvitaminD [25(OH)D], an active metabolite of vitamin D, in a cohort of at-risk first-degree relatives (FDR) of INA RA patients, a subset of whom subsequently developed RA (progressors). METHODS:2007 onward, serum samples from INA RA patients and FDR were collected at the time of a structured baseline visit and stored at -20°C. Anti-citrullinated protein antibodies (ACPA), 25(OH)D, hs-CRP, vitamin-D binding protein (VDBP) and parathyroid hormone (PTH) levels were determined using ELISA and rheumatoid factor (RF) seropositivity was determined by nephelometry. RESULTS:We demonstrate that 25 (OH) D concentrations were lower in winter than summer (P = 0.0538), and that serum 25(OH)D levels were higher in samples collected and stored after 2013 (P<0.0001). Analysis of samples obtained after 2013 demonstrated that 37.6% of study participants were 25(OH)D insufficient (<75nmol/L). Also, seropositive RA patients and FDR had lower 25(OH)D levels compared to ACPA-/FDR (P<0.05, P<0.01 respectively). Linear regression analysis showed 25(OH)D insufficiency was inversely associated with presence of RA autoantibodies. Longitudinal samples from 14 progressors demonstrated a consistent increase in 25(OH)D levels at the time they exhibited clinically detectable joint inflammation, without any significant change in VDBP or PTH levels. Spearman rank correlation analysis showed significant association between 25(OH)D and PTH levels, both in RA patients and progressors at RA onset time. CONCLUSION:We demonstrate that 25(OH)D levels in serum increased at RA onset in progressors. The potential role that vitamin D metabolites and their downstream effects play in RA transition requires further investigation