Synthetic Immunomodulatory Peptide IDR-1002 Enhances Monocyte Migration and Adhesion on Fibronectin

Abstract

Regulation of the immune system by immunomodulatory agents, such as the synthetic innate defense regulator (IDR) peptides, has been proposed as a potential strategy to strengthen host immune responses against infection. IDR peptides confer protection in vivo against a range of bacterial infections and have been developed as components of single-dose vaccine adjuvants due to their ability to modulate innate immunity, correlating with an increased recruitment of monocytes to sites of infection or immunization. However, the mechanisms by which IDR peptides augment monocyte recruitment remain poorly defined. Anti-infective peptide IDR-1002 was demonstrated here to lack direct monocyte chemoattractive activity yet enhance, by up to 5-fold, the ability of human monocytes to migrate on fibronectin towards chemokines. This effect correlated with an increased adhesion of monocytes and THP-1 cells to fibronectin by IDR-1002 and other IDR peptides and the adhesion of THP-1 cells to fibronectin occurred in a β₁-integrin-dependent manner, corresponding with an increased activation of β₁-integrins and the phosphoinositide 3-kinase (PI3K)-Akt pathway. PI3K- and Akt-specific inhibitors abrogated IDR-1002-induced adhesion and activation of β₁-integrins, whereas p38 and MEK1 inhibitors did not affect, or moderately inhibited, adhesion, respectively. Furthermore, IDR-1002 enhancement of monocyte migration towards chemokines and activation of β₁-integrins was abrogated in the presence of PI3K- and Akt-specific inhibitors. In summary, IDR-1002 enhanced monocyte migration on fibronectin through promotion of β₁-integrin-mediated interactions regulated by the PI3K-Akt pathway, revealing a mechanism by which IDR-1002 promotes monocyte recruitment.

Anti-infective peptide IDR-1002 augments monocyte chemotaxis towards CCR5 chemokines

“…In contrast, peptide-stimulated monocytes exhibited significantly stronger chemotactic activity towards CCL3 and CCL5 at nearly all chemokine concentrations tested. IDR-1002 stimulation in the absence of chemokines had no effect on baseline monocyte migration, confirming a previous study that showed the lack of direct chemokinetic properties of this peptide on monocytes [5]. Overall, these results demonstrated that IDR-1002 could selectively enhance monocyte migration towards chemokines CCL3 and CCL5.…”

“…Thus to understand the anti-infective nature of IDR-peptides, we sought to elucidate the mechanisms through which they enhance monocyte recruitment. In a previous study, we determined that IDR-1002, a peptide with no direct chemotactic or chemokinetic effects, augments monocyte migration through a fibronectin network via the promotion of b1-integrin-mediated adhesion [5]. Observations in this study also implicated an adhesion-independent, chemokine-specific mechanism utilized by IDR-1002 to promote monocyte recruitment.…”

“…We propose that this effect stems from the selective promotion of CCR5 expression on monocyte surfaces and a potential reinforcement of chemokine-mediated signal transduction pathways. This study not only reveals a novel regulatory axis of IDR-1002 on monocyte mobilization, in addition to the known enhancement of b1-integrin-mediated monocyte adhesion and induction of chemokine production [5], but also presents a novel avenue through which IDR-peptides might regulate anti-infective host defences. Synergy between IDR-1002 and chemokines, may have noteworthy ramifications on the anti-infective immune response.…”

Intranasal treatment with a novel immunomodulator mediates innate immune protection against lethal pneumonia virus of mice

“…IDR peptide 1002 is a synthetic cationic peptide derived from bovine bactenecin, a 12-amino-acid cathelicidin produced by bovine neutrophils [110][111][112]. Many research of angiogenesis and wound healing [110,113,114].…”

“…Many research of angiogenesis and wound healing [110,113,114]. There is evidence suggesting that IDR peptide 1002 is a better inducer of chemokines in vitro than IDR-1, another wellknown bactenecin-derived peptide [110,111,113]. In addition, IDR peptide 1002 protected mice against invasive Staphylococcus aureus and Escherichia coli infections by enhancing monocyte and neutrophil recruitment into the site of infection [110,111,113].…”