Abstract
Inflammation in now appreciated to be at the centre of may diseases that affect Western civilization. Current therapeutics for managing these conditions may interfere with the host response leading to immune suppression. We recently developed an annexin (Anx) A1-derived peptide, coined CR-AnxA12-50, which displays potent pro-resolving and tissue protective actions. Herein, we designed a novel peptide using CR-AnxA12-50 as a template that was significantly more resistant to neutrophil-mediated degradation. This peptide, termed CR-AnxA12-48, retained high affinity and specificity to the pro-resolving Lipoxin A4 receptor (ALX) with an IC50 of ~20nM. CR-AnxA12-48 dose dependently (100fM-10nM) promoted the efferocytosis of apoptotic neutrophils, an action that was mediated by the murine orthologue of human ALX. The neutrophil-directed actions were also retained with human primary cells were CR-AnxA12-48 reduced human neutrophil recruitment to activated endothelial cells at concentrations as low as 100 pM. This protective action was mediated by human ALX, since incubation of neutrophils with an anti-ALX antibody reversed this anti-inflammatory actions of CR-AnxA12-48. Administration of this peptide to mice during dermal inflammation led to a significant and dose dependent decrease in neutrophil recruitment. This reduction in neutrophil numbers was more pronounced than that displayed by the parent peptide CR-AnxA12-50. CR-AnxA12-48 was also cardioprotecitve reducing infarct size and systemic chemokine (C-C motif) ligand 5 concentration following ischemia reperfusion injury. These findings identify CR-AnxA12-48 as a new ALX agonist that regulates phagocyte responses and displays tissue-protective actions.
Highlights
Inflammation is intrinsically host protective [1]
Together these findings demonstrate that CR-AnxA12-48 displays potent leukocyte directed anti-inflammatory and pro-resolving actions that are mediated by the receptor ALX
In the present study we characterized the biological actions of a novel Annexin A1 (AnxA1)-derived peptide
Summary
Inflammation is intrinsically host protective [1]. Recent evidence suggests that when resolution mechanisms become dysregulated the inflammatory response may be perpetuated leading to unabated inflammation and tissue destruction [2, 3]. It is well appreciated that in self-limited inflammation, i.e. when inflammation does not progress to chronicity, the body engages mechanisms that actively downregulate the production of inflammatory mediators as well as the clearance of leukocytes and cellular debris from the site of inflammation [8, 9] In this context several families of molecules including specialized pro-resolving mediators [9], gaseous mediators (e.g. carbon monoxide [10] and hydrogen sulphide [11]) and proteins were recently described to regulate various aspects of the inflammation-resolution process. This peptide, coined, CR-AnxA12-50, binds and activates the AnxA1 cognate receptor with a high degree of selectivity and specificity It retained the anti-inflammatory and pro-resolving actions of the parent protein, regulating neutrophil recruitment to the site of sterile inflammation in mice and neutrophil endothelial interactions with primary human cells. The novel peptide displayed potent cardioprotecive actions in murine cardiac reperfusion injury
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