CD19 Regulates Skin and Lung Fibrosis via Toll-Like Receptor Signaling in a Model of Bleomycin-Induced Scleroderma

Ayumi Yoshizaki^*, Yohei Iwata^*, Kazuhiro Komura^*, Fumihide Ogawa^*, Toshihide Hara^*, Eiji Muroi^*, Motoi Takenaka^*, Kazuhiro Shimizu^*, Minoru Hasegawa, Manabu Fujimoto, Thomas F. Tedder and Shinichi Sato^*

From the Department of Dermatology,^* Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; the Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; and the Department of Immunology, Duke University Medical Center, Durham, North Carolina

Mice subcutaneously injected with bleomycin, in an experimentalmodel of human systemic sclerosis, develop cutaneous and lungfibrosis with autoantibody production. CD19 is a general "rheostat"that defines signaling thresholds critical for humoral immuneresponses, autoimmunity, and cytokine production. To determinethe role of CD19 in the bleomycin-induced systemic sclerosismodel, we investigated the development of fibrosis and autoimmunityin CD19-deficient mice. Bleomycin-treated wild-type mice exhibiteddermal and lung fibrosis, hyper- ${gamma}$ -globulinemia, autoantibodyproduction, and enhanced serum and skin expression of variouscytokines, including fibrogenic interleukin-4, interleukin-6,and transforming growth factor-β1, all of which were inhibitedby CD19 deficiency. Bleomycin treatment enhanced hyaluronanproduction 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 throughTLR4; CD19 deficiency suppressed this stimulation. These resultssuggest that bleomycin induces fibrosis by enhancing hyaluronanproduction, which activates B cells to produce fibrogenic cytokinesmainly via TLR4 and induce autoantibody production, and thatCD19 deficiency suppresses fibrosis and autoantibody productionby inhibiting TLR4 signals.