CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma.
Mice subcutaneously injected with bleomycin, in an experimental model of human systemic sclerosis, develop cutaneous and lung fibrosis with autoantibody production. CD19 is a general "rheostat" that defines signaling thresholds critical for humoral immune responses, autoimmunity, and cytokine production. To determine the role of CD19 in the bleomycin-induced systemic sclerosis model, we investigated the development of fibrosis and autoimmunity in CD19-deficient mice. Bleomycin-treated wild-type mice exhibited dermal and lung fibrosis, hyper-gamma-globulinemia, autoantibody production, and enhanced serum and skin expression of various cytokines, including fibrogenic interleukin-4, interleukin-6, and transforming growth factor-beta1, all of which were inhibited by CD19 deficiency. Bleomycin treatment enhanced hyaluronan production in the skin, lung, and sera. Addition of hyaluronan, an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4, stimulated B cells to produce various cytokines, primarily through TLR4; CD19 deficiency suppressed this stimulation. These results suggest that bleomycin induces fibrosis by enhancing hyaluronan production, which activates B cells to produce fibrogenic cytokines mainly via TLR4 and induce autoantibody production, and that CD19 deficiency suppresses fibrosis and autoantibody production by inhibiting TLR4 signals.
Yoshizaki
Ayumi
A
Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
Iwata
Yohei
Y
Komura
Kazuhiro
K
Ogawa
Fumihide
F
Hara
Toshihide
T
Muroi
Eiji
E
Takenaka
Motoi
M
Shimizu
Kazuhiro
K
Hasegawa
Minoru
M
Fujimoto
Manabu
M
Tedder
Thomas F
TF
Sato
Shinichi
S
D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001761:Bleomycin; D016207:Cytokines / Q000096:biosynthesis; D005355:Fibrosis; D006820:Hyaluronic Acid / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D012867:Skin / Q000473:pathology*; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D018941:Antigens, CD19; D001323:Autoantibodies; D016207:Cytokines; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D001761:Bleomycin; D006820:Hyaluronic Acid