title: Vesicular LL-37 contributes to inflammation of the lesional skin of palmoplantar pustulosis.
abstract: "Pustulosis palmaris et plantaris", or palmoplantar pustulosis (PPP), is a chronic pustular dermatitis characterized by intraepidermal palmoplantar pustules. Although early stage vesicles (preceding the pustular phase) formed in the acrosyringium contain the antimicrobial peptides cathelicidin (hCAP-18/LL-37) and dermcidin, the details of hCAP-18/LL-37 expression in such vesicles remain unclear. The principal aim of the present study was to clarify the manner of hCAP-18/LL-37 expression in PPP vesicles and to determine whether this material contributed to subsequent inflammation of lesional skin. PPP vesicle fluid (PPP-VF) induced the expression of mRNAs encoding IL-17C, IL-8, IL-1α, and IL-1β in living skin equivalents, but the level of only IL-8 mRNA decreased significantly upon stimulation of PPP vesicle with depletion of endogenous hCAP-18/LL-37 by affinity chromatography (dep-PPP-VF). Semi-quantitative dot-blot analysis revealed higher concentrations of hCAP-18/LL-37 in PPP-VF compared to healthy sweat (2.87±0.93 µM vs. 0.09±0.09 µM). This concentration of hCAP-18/LL-37 in PPP-VF could upregulate expression of IL-17C, IL-8, IL-1α, and IL-1β at both the mRNA and protein levels. Recombinant hCAP-18 was incubated with dep-PPP-VF. Proteinase 3, which converts hCAP-18 to the active form (LL-37), was present in PPP-VF. Histopathological and immunohistochemical examination revealed that early stage vesicles contained many mononuclear cells but no polymorphonuclear cells, and the mononuclear cells were CD68-positive. The epidermis surrounding the vesicle expresses monocyte chemotactic chemokine, CCL2. In conclusion, PPP-VF contains the proteinase required for LL-37 processing and also may directly upregulate IL-8 in lesional keratinocytes, in turn contributing to the subsequent inflammation of PPP lesional skin.
authors.affiliation: Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Masamoto
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Department of Dermatology, Asahikawa Medical College, Asahikawa, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: Division of Dermatology, University of California San Diego, and VA San Diego Healthcare Center, San Diego, California, United States of America.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Nakatsuji
authors.affiliation: Integrated Center for Science, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kameda
authors.affiliation: Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Okazaki
authors.affiliation: Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Xiuju
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Hanakawa
authors.affiliation: Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Tohyama
authors.affiliation: Department of Dermatology, Asahikawa Medical College, Asahikawa, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Ishida-Yamamoto
authors.affiliation: Department of Dermatology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sayama
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013545:Sweat Glands / Q000378:metabolism / Q000473:pathology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D016209:Interleukin-8; D012333:RNA, Messenger; D054804:Cathelicidins