MPO-ANCA induces IL-17 production by activated neutrophils in vitro via classical complement pathway-dependent manner.
The elevation of serum anti-neutrophil cytoplasmic autoantibodies (ANCA) is significantly associated with the progression of some patients with systemic vasculitis. Especially, myeloperoxidase-specific ANCA (MPO-ANCA) play a pivotal role in the progression of systemic vasculitis including crescentic glomerulonephritis. Here we demonstrated that MPO-ANCA-activated neutrophils allow the local environment to differentiate Th(17) cells through IL-6, IL-17A, and IL-23 production. We found a variety of elevated serum cytokines, especially IL-17A, in ANCA-mediated systemic vasculitis mice. Furthermore, activated peritoneal neutrophils in vitro also produced IL-17A and IL-23 in response to MPO-ANCA. Co-stimulation of fungal mannoprotein and complements significantly enhanced the MPO-ANCA-mediated IL-17A expression, but F(ab)'(2) fragments of MPO-ANCA diminished the cytokine response. These results suggest that the activated neutrophils produce IL-17A and IL-23 in response to MPO-ANCA via their Fc-region and classical complement pathway, which initiate the first steps of chronic autoimmune inflammation by allowing the local environment to develop Th(17)-mediated autoimmunity.
Hoshino
Akiyoshi
A
International Clinical Research Center, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Nagao
Tomokazu
T
Nagi-Miura
Noriko
N
Ohno
Naohito
N
Yasuhara
Masato
M
Yamamoto
Kenji
K
Nakayama
Toshinori
T
Suzuki
Kazuo
K
D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology; D002478:Cells, Cultured; D003171:Complement Pathway, Classical / Q000187:drug effects / Q000276:immunology*; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D009195:Peroxidase / Q000276:immunology; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism
D019268:Antibodies, Antineutrophil Cytoplasmic; D001323:Autoantibodies; D020381:Interleukin-17; D008562:Membrane Glycoproteins; C025363:mannoproteins; D009195:Peroxidase