Novel Sulfated Polysaccharides Disrupt Cathelicidins, Inhibit RAGE and Reduce Cutaneous Inflammation in a Mouse Model of Rosacea

Abstract

BackgroundRosacea is a common disfiguring skin disease of primarily Caucasians characterized by central erythema of the face, with telangiectatic blood vessels, papules and pustules, and can produce skin thickening, especially on the nose of men, creating rhinophyma. Rosacea can also produce dry, itchy eyes with irritation of the lids, keratitis and corneal scarring. The cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37.Methodology/Principal FindingsWe tested a new class of non-anticoagulant sulfated anionic polysaccharides, semi-synthetic glycosaminoglycan ethers (SAGEs) on key elements of the pathogenic pathway leading to rosacea. SAGEs were anti-inflammatory at ng/ml, including inhibition of polymorphonuclear leukocyte (PMN) proteases, P-selectin, and interaction of the receptor for advanced glycation end-products (RAGE) with four representative ligands. SAGEs bound LL-37 and inhibited interleukin-8 production induced by LL-37 in cultured human keratinocytes. When mixed with LL-37 before injection, SAGEs prevented the erythema and PMN infiltration produced by direct intradermal injection of LL-37 into mouse skin. Topical application of a 1% (w/w) SAGE emollient to overlying injected skin also reduced erythema and PMN infiltration from intradermal LL-37.ConclusionsAnionic polysaccharides, exemplified by SAGEs, offer potential as novel mechanism-based therapies for rosacea and by extension other LL-37-mediated and RAGE-ligand driven skin diseases.

Increased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients

“…However, most studies that suggest RAGE as a receptor for LL37 provide indirect evidence [5,12,13]. Nevertheless, we observed that the LL37-induced interleukin-8 production by human bronchial epithelial cells can be partly inhibited by RAGE-antagonistic peptide (data not shown).…”

Isolevuglandin-Type Lipid Aldehydes Induce the Inflammatory Response of Macrophages by Modifying Phosphatidylethanolamines and Activating the Receptor for Advanced Glycation Endproducts

“…To test whether RAGE was required for IsoLG-PE-induced signaling, we examined the effect of two RAGE antagonists with differing modes of action on IsoLG-PE activation of macrophages. We found that GM-0111, a synthetic glycosaminoglycan previously shown to act as an RAGE antagonist (73), significantly inhibited IsoLG-PE-induced NFjB reporter activity (Fig. 7B).…”

Topical cathelicidin (LL‐37) an innate immune peptide induces acute olfactory epithelium inflammation in a mouse model

“…27 In addition, both LL-37 and RAGE are highly elevated in patients with chronic sinonasal inflammation. 9,23 This pathway is not unique to the sinuses, as the RAGE pathway has been elucidated in many other chronic inflammatory diseases, including, but not limited to, rosacea, 27 arthritis, 42 and interstitial cystitis. 30 Further investigations are needed to define LL-37-RAGE induced upper airway inflammation.…”

“…21,27 Heads were bisected in a sagittal plane at the nasal septum and the mucosa evaluated for gross differences. The bisected sections were randomly assigned to either histology/immunohistochemistry or sinus tissue processing.…”