TY - JOUR
T1 - Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases
AU - Chirivi, Renato G.S.
AU - van Rosmalen, Jos W.G.
AU - van der Linden, Maarten
AU - Euler, Maximilien
AU - Schmets, Gonny
AU - Bogatkevich, Galina
AU - Kambas, Konstantinos
AU - Hahn, Jonas
AU - Braster, Quinte
AU - Soehnlein, Oliver
AU - Hoffmann, Markus H.
AU - Es, Helmuth H.G.van
AU - Raats, Jos M.H.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2021/6
Y1 - 2021/6
N2 - Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.
AB - Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.
UR - http://www.scopus.com/inward/record.url?scp=85082848650&partnerID=8YFLogxK
U2 - 10.1038/s41423-020-0381-3
DO - 10.1038/s41423-020-0381-3
M3 - Journal articles
C2 - 32203195
AN - SCOPUS:85082848650
SN - 1672-7681
VL - 18
SP - 1528
EP - 1544
JO - Cellular and Molecular Immunology
JF - Cellular and Molecular Immunology
IS - 6
ER -