Osteopontin in spontaneous germinal centers inhibits apoptotic cell engulfment and promotes anti-nuclear antibody production in lupus-prone mice

Keiko Sakamoto, Yuji Fukushima, Koyu Ito, Michiyuki Matsuda, Shigekazu Nagata, Nagahiro Minato, Masakazu Hattori

研究成果: Article査読

23 被引用数 (Scopus)

抄録

Disposal of apoptotic cells is important for tissue homeostasis. Defects in this process in immune tissues may lead to breakdown of self-tolerance against intracellular molecules, including nuclear components. Development of diverse anti-nuclear Abs (ANAs) is a hallmark of lupus, which may arise, in part, due to impaired apoptotic cell clearance. In this work, we demonstrate that spontaneous germinal centers (GCs) in lupus-prone mice contain significantly elevated levels of unengulfed apoptotic cells, which are otherwise swiftly engulfed by tingible body macrophages. We indicate that osteopontin (OPN) secreted by CD153+ senescence-associated T cells, which selectively accumulate in the GCs of lupus-prone mice, interferes with phagocytosis of apoptotic cells specifically captured via MFG-E8. OPN induced diffuse and prolonged Rac1 activation in phagocytes via integrin avb3 and inhibited the dissolution of phagocytic actin cup, causing defective apoptotic cell engulfment. In wild-type B6 mice, administration of TLR7 ligand also caused spontaneous GC reactions with increasing unengulfed apoptotic cells and ANA production, whereas B6 mice deficient for Spp1 encoding OPN showed less apoptotic cells and developed significantly reduced ANAs in response to TLR7 ligand. Our results suggest that OPN secreted by follicular CD153+ senescence-associated T cells in GCs promotes a continuous supply of intracellular autoantigens via apoptotic cells, thus playing a key role in the progression of the autoreactive GC reaction and leading to pathogenic autoantibody production in lupus-prone mice.

本文言語English
ページ(範囲)2177-2186
ページ数10
ジャーナルJournal of Immunology
197
6
DOI
出版ステータスPublished - 2016 9 15
外部発表はい

ASJC Scopus subject areas

  • 免疫アレルギー学
  • 免疫学

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