Severe thymic atrophy in a mouse model of skin inflammation accounts for impaired TNFR1 signaling.
Transgenic mice expressing the caspase-cleaved form of the tyrosine kinase Lyn (LynΔN) develop a TNFα-dependent skin disease that accurately recapitulates human psoriasis. Participation of lymphocytes in this disease was confirmed by backcrossing LynΔN mice on a Rag-1 deficient background. The present study was therefore conducted to analyze whether modification of lymphocyte homeostasis does occur and participate in the phenotype of LynΔN mice. We show here that LynΔN mice consistently exhibit thymic atrophy that correlates with both a net decrease in the CD4+/CD8+ Double Positive (DP) and an increase in Single Positive (SP) thymocyte sub-populations, but also display an increase of splenic mature B cell. Interestingly, a normal immune phenotype was rescued in a TNFR1 deficient background. Finally, none of these immune alterations was detected in newborn mice before the onset of inflammation. Therefore, we conclude that chronic inflammation can induce thymic atrophy and perturb spleen homeostasis in LynΔN mice through the increased production of TNFα, LTß and TNFR1 signaling.
Inserm, UMR 1065, Centre Méditerranéen de Médecine Moléculaire, Team Cell death, differentiation, inflammation and cancer, Nice, France.
Nathalie
N
Belhacéne
Parvati
P
Gamas
Diogo
D
Gonçalvès
Marie
M
Jacquin
Marie
M
Beneteau
Arnaud
A
Jacquel
Pascal
P
Colosetti
Jean-Ehrland
JE
Ricci
Abdellilah
A
Wakkach
Patrick
P
Auberger
Sandrine
S
Marchetti
D000818:Animals; D001284:Atrophy / Q000503:physiopathology; D001402:B-Lymphocytes / Q000166:cytology; D001973:Bromodeoxyuridine; D003872:Dermatitis / Q000235:genetics / Q000503:physiopathology*; D005434:Flow Cytometry; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics*
D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D001973:Bromodeoxyuridine