Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea.
Rosacea is a chronic inflammatory skin disease whose pathophysiological mechanism is still unclear. However, it is known that mast cell (MC) numbers are increased in the dermis of rosacea patients. MC proteases not only recruit other immune cells, which amplify the inflammatory response, but also cause vasodilation and angiogenesis. MCs are also one of the primary sources of cathelicidin LL-37 (Cath LL-37), an antimicrobial peptide that has been shown to be an enabler of rosacea pathogenesis. Here, we demonstrate that MCs are key mediators of cathelicidin-initiated skin inflammation. After Cath LL-37 injection into the dermis, MC-deficient B6.Cg-Kit(W-sh)/HNihrJaeBsmJ (KitW-sh) mice did not develop rosacea-like features. Conversely, chymase (P<0.001), tryptase, and Mmp9 (P<0.01) mRNA levels were significantly higher in C57BL/6 wild-type (WT) mice. Treating WT mice with an MC stabilizer significantly decreased the expressions of Mmp9 and Cxcl2 (P<0.01). Our data were confirmed on erythematotelangiectatic rosacea subjects who showed a decrease in matrix metalloproteinase activity (P<0.05), after 8 weeks of topical cromolyn treatment. We conclude that MCs have a central role in the development of inflammation subsequent to Cath LL-37 activation and that downregulation of activated MCs may be a therapy for rosacea treatment.
Division of Dermatology, Department of Medicine, University of California, San Diego, San Diego, California, USA.
Yumiko
Y
Muto
Division of Dermatology, Department of Medicine, University of California, San Diego, San Diego, California, USA.
Zhenping
Z
Wang
Division of Dermatology, Department of Medicine, University of California, San Diego, San Diego, California, USA.
Matthieu
M
Vanderberghe
Division of Dermatology, Department of Medicine, University of California, San Diego, San Diego, California, USA.
Aimee
A
Two
Division of Dermatology, Department of Medicine, University of California, San Diego, San Diego, California, USA.
Richard L
RL
Gallo
Division of Dermatology, Department of Medicine, University of California, San Diego, San Diego, California, USA. Electronic address: adinardo@ucsd.edu.
Anna
A
Di Nardo
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D053818:Chymases / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000139:chemically induced; D015850:Interleukin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D008407:Mast Cells / Q000166:cytology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012393:Rosacea / Q000276:immunology* / Q000378:metabolism*; D012867:Skin / Q000276:immunology* / Q000378:metabolism*; D053802:Tryptases / Q000378:metabolism; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D015850:Interleukin-6; D053818:Chymases; D053802:Tryptases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D054804:Cathelicidins