THU0220 PEPTIDYLARGININE DEIMINASE 4 DEFICIENCY AMELIORATED A MURINE MODEL OF LUPUS BY REDUCING NEUTROPHIL MIGRATION TO THE KIDNEY
Authors: Norio Hanata, Hirofumi Shoda, Hiroaki Hatano, Yasuo Nagafuchi, Toshihiko Komai, Tomohisa Okamura, Akari Suzuki, Kazuhiko Yamamoto, Keishi Fujio
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> 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. <h3>Objectives:</h3> We set to determine the pathological role of neutrophils and PADI4 in SLE using <i>Padi4</i> knock out (KO) mice. <h3>Methods:</h3> 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 <i>Padi4</i> 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 <i>in vivo</i>, and adherence assays <i>in vitro</i>. <h3>Results:</h3> Compared with IMQ-treated WT (WT-IMQ) mice, <i>Padi4</i> KO-IMQ mice showed decreased spleen weight. Moreover, proteinuria, and dermatitis were not exacerbated in the <i>Padi4</i> 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 <i>Padi4</i> 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 <i>Padi4</i> KO-IMQ mice. In the adoptive transfer experiment, there was a significant decrease in the transferred <i>Padi4</i> 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 <i>Padi4</i> KO neutrophils primed by the TLR7 agonist. <h3>Conclusion:</h3> Nephritis was ameliorated in <i>Padi4</i> 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. <h3>Disclosure of Interests:</h3> 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.