title: Granzyme A potentiates chemokine production in IL-17-stimulated keratinocytes.
abstract: Plaque psoriasis presents with focal skin inflammation, partially maintained by IL-17-mediated interactions between infiltrating epidermal T cells and activated keratinocytes. Here we show that the majority of lesional epidermal CD8 T cells express granzyme A, alone or in combination with IL-17. To assess proinflammatory properties of granzyme A in psoriasis, primary human keratinocytes were stimulated with granzyme A in the presence or absence of IL-17. Out of 33 analysed keratinocyte-derived inflammatory mediators, granzyme A potentiated IL-17-induced secretion of CXCL 1, CXCL 12 and CCL 4. Intriguingly, all three chemokines are implicated in psoriasis pathogenesis and are involved in recruitment of T cells, neutrophils and pDCs into inflamed tissues. Our results indicate that granzyme A produced by lesional CD8 T cells specifically increase the chemokine production from inflamed keratinocytes, thereby amplifying a chemotactic inflammatory loop that sustains psoriasis lesions.
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Stanley
authors.initials: S
authors.lastname: Cheuk
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Elisa
authors.initials: E
authors.lastname: Martini
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bergh
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Chang
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Bence
authors.initials: B
authors.lastname: Rethi
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Mona
authors.initials: M
authors.lastname: Ståhle
authors.affiliation: Dermatology and Venereology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Liv
authors.initials: L
authors.lastname: Eidsmo
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology*; D016022:Case-Control Studies; D005260:Female; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000201:enzymology / Q000276:immunology*
chemical_list: D020381:Interleukin-17; D053804:Granzymes
keywords: T cells; cytotoxic granules; inflammation; psoriasis; serine proteases