The caspase-cleaved form of LYN mediates a psoriasis-like inflammatory syndrome in mice.
We showed previously that Lyn is a substrate for caspases, a family of cysteine proteases, involved in the regulation of apoptosis and inflammation. Here, we report that expression of the caspase-cleaved form of Lyn (LynDeltaN), in mice, mediates a chronic inflammatory syndrome resembling human psoriasis. Genetic ablation of TNF receptor 1 in a LynDeltaN background rescues a normal phenotype, indicating that LynDeltaN mice phenotype is TNF-alpha-dependent. The predominant role of T cells in the disease occurring in LynDeltaN mice was highlighted by the distinct improvement of LynDeltaN mice phenotype in a Rag1-deficient background. Using pan-genomic profiling, we also established that LynDeltaN mice show an increased expression of STAT-3 and inhibitory members of the NFkappaB pathway. Accordingly, LynDeltaN alters NFkappaB activity underlying a link between inhibition of NFkappaB and LynDeltaN mice phenotype. Finally, analysis of Lyn expression in human skin biopsies of psoriatic patients led to the detection of Lyn cleavage product whose expression correlates with the activation of caspase 1. Our data identify a new role for Lyn as a regulator of psoriasis through its cleavage by caspases.
Marchetti
Sandrine
S
INSERM, U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 2, Nice, France.
Gamas
Parvati
P
Belhacène
Nathalie
N
Grosso
Sebastien
S
Pradelli
Ludivine A
LA
Colosetti
Pascal
P
Johansen
Claus
C
Iversen
Lars
L
Deckert
Marcel
M
Luciano
Fréderic
F
Hofman
Paul
P
Ortonne
Nicolas
N
Khemis
Abdallah
A
Mari
Bernard
B
Ortonne
Jean-Paul
JP
Ricci
Jean-Ehrland
JE
Auberger
Patrick
P
D000818:Animals; D001706:Biopsy; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000033:anatomy & histology / Q000473:pathology*; D013950:Thymus Gland / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism*
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D020169:Caspases