THU0220 PEPTIDYLARGININE DEIMINASE 4 DEFICIENCY AMELIORATED A MURINE MODEL OF LUPUS BY REDUCING NEUTROPHIL MIGRATION TO THE KIDNEY

Background: Peptidylarginine deiminase 4 (PADI4) is reported to play several biological roles in neutrophils, including neutrophil extracellular trap formation, apoptosis, and epigenetic regulation. Neutrophils could play pivotal roles in the pathogenesis of SLE. Objectives: We set to determine the pathological role of neutrophils and PADI4 in SLE using Padi4 knock out (KO) mice. Methods: A murine model of imiquimod (IMQ)-induced lupus was analyzed. A TLR7 agonist, IMQ, was administered topically to the ear skin of B6 wild-type (WT) and Padi4 KO mice. Proteinuria, spleen weight, serum anti-dsDNA level, frequencies of spleen and renal immune cells, and the histopathological findings of ear skin and kidney, were assessed. Neutrophil migration and adhesion were evaluated by adoptive transfer experiments in vivo, and adherence assays in vitro. Results: Compared with IMQ-treated WT (WT-IMQ) mice, Padi4 KO-IMQ mice showed decreased spleen weight. Moreover, proteinuria, and dermatitis were not exacerbated in the Padi4 KO-IMQ mice. There was a positive correlation between the frequency of kidney neutrophils and the degree of proteinuria, while significant decreases in kidney neutrophils were noted in the Padi4 KO-IMQ mice. Notably, the elevation of serum anti-dsDNA levels, or the degree of immune complex deposition in the kidney, showed no significant difference between the WT-IMQ and Padi4 KO-IMQ mice. In the adoptive transfer experiment, there was a significant decrease in the transferred Padi4 KO neutrophil infiltrations in the kidney compared with those of WT neutrophils. The frequency of adhesive neutrophils toward ICAM-1 was significantly decreased in the Padi4 KO neutrophils primed by the TLR7 agonist. Conclusion: Nephritis was ameliorated in Padi4 KO-IMQ mice. Our study shed light on the importance of neutrophils in the pathogenesis of SLE, and the suppression of neutrophil function by inhibition of PADI4 will be a unique therapeutic strategy for SLE. Disclosure of Interests: Norio Hanata: None declared, Hirofumi Shoda Speakers bureau: Astellas, Abbie, BMS, GSK, Daiichi-Sankyo, Pfizer, Chugai, UCB, Eli Lilly., Hiroaki Hatano: None declared, Yasuo Nagafuchi Grant/research support from: BMS, Chugai., Speakers bureau: BMS, Pfizer, Kissei., Toshihiko Komai Grant/research support from: GlaxoSmithKline., Tomohisa Okamura Grant/research support from: Chugai, Novartis., Akari Suzuki Grant/research support from: Takeda, Chugai, Pfizer., Kazuhiko Yamamoto Grant/research support from: Astellas, BMS, Daiichi-Sankyo, Mitsubishi Tanabe, Pfizer, Ayumi, Takeda, Chugai, Eisai, Taisho Toyama, UCB, Janssen, Eli Lilly, and NIPPON KAYAKU., Speakers bureau: Astellas, BMS, Daiichi-Sankyo, Mitsubishi Tanabe, Pfizer, Ayumi, Takeda, Chugai, Eisai, Taisho Toyama, UCB, Janssen, Eli Lilly, and NIPPON KAYAKU., Keishi Fujio Grant/research support from: Astellas, BMS, Daiichi-Sankyo, Mitsubishi Tanabe, Pfizer, Ayumi, Takeda, Chugai, Eisai, Taisho Toyama, UCB, Janssen, Eli Lilly, and NIPPON KAYAKU., Speakers bureau: Astellas, BMS, Daiichi-Sankyo, Mitsubishi Tanabe, Pfizer, Ayumi, Takeda, Chugai, Eisai, Taisho Toyama, UCB, Janssen, Eli Lilly, and NIPPON KAYAKU.