Abstract
Innate defense regulators (IDRs) are synthetic immunomodulatory versions of natural host defense peptides (HDP). IDRs mediate protection against bacterial challenge in the absence of direct antimicrobial activity, representing a novel approach to anti-infective and anti-inflammatory therapy. Previously, we reported that IDR-1018 selectively induced chemokine responses and suppressed pro-inflammatory responses. As there has been an increasing appreciation for the ability of HDPs to modulate complex immune processes, including wound healing, we characterized the wound healing activities of IDR-1018 in vitro. Further, we investigated the efficacy of IDR-1018 in diabetic and non-diabetic wound healing models. In all experiments, IDR-1018 was compared to the human HDP LL-37 and HDP-derived wound healing peptide HB-107. IDR-1018 was significantly less cytotoxic in vitro as compared to either LL-37 or HB-107. Furthermore, administration of IDR-1018 resulted in a dose-dependent increase in fibroblast cellular respiration. In vivo, IDR-1018 demonstrated significantly accelerated wound healing in S. aureus infected porcine and non-diabetic but not in diabetic murine wounds. However, no significant differences in bacterial colonization were observed. Our investigation demonstrates that in addition to previously reported immunomodulatory activities IDR-1018 promotes wound healing independent of direct antibacterial activity. Interestingly, these effects were not observed in diabetic wounds. It is anticipated that the wound healing activities of IDR-1018 can be attributed to modulation of host immune pathways that are suppressed in diabetic wounds and provide further evidence of the multiple immunomodulatory activities of IDR-1018.
Highlights
Cutaneous wound repair is a specialized, multifactorial process that involves a large number of factors that are involved in the regulation of this process [1]
Effects of Innate defense regulators (IDRs)-1018 on cell viability and migration To investigate of effects of IDR-1018 on cell oxidative metabolism, an MTT-Assay was performed on HaCaT and primary human fibroblasts (HFB)
IDR-1018 treated HaCaT cells maintained cell viability better than those treated with LL-37 or HB-107 at all concentrations analyzed in this study (Fig. 1)
Summary
Cutaneous wound repair is a specialized, multifactorial process that involves a large number of factors that are involved in the regulation of this process [1]. The immunomodulatory activities of such natural peptides, especially the human cathelicidin LL-37 and human b-defensin (hBD) -3, are extremely diverse and include, but are not limited to, the stimulation of epithelial cell migration, promotion of angiogenesis, and suppression of pro-inflammatory responses [3,5,6,7,8]. HDPs have been implicated as regulators of cutaneous wound repair by regulating inflammation, angiogenesis, and extracellular tissue deposition and remodeling [3,15,16,17,18]
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