Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis
JournalJournal of Experimental Medicine
PublisherRockefeller University Press
MetadataShow full item record
AbstractHeart failure due to dilated cardiomyopathy is frequently caused by myocarditis. However, the pathogenesis of myocarditis remains incompletely understood. Here, we report the presence of neutrophil extracellular traps (NETs) in cardiac tissue of patients and mice with myocarditis. Inhibition of NET formation in experimental autoimmune myocarditis (EAM) of mice substantially reduces inflammation in the acute phase of the disease. Targeting the cytokine midkine (MK), which mediates NET formation in vitro, not only attenuates NET formation in vivo and the infiltration of polymorphonuclear neutrophils (PMNs) but also reduces fibrosis and preserves systolic function during EAM. Low-density lipoprotein receptor–related protein 1 (LRP1) acts as the functionally relevant receptor for MK-induced PMN recruitment as well as NET formation. In summary, NETosis substantially contributes to the pathogenesis of myocarditis and drives cardiac inflammation, probably via MK, which promotes PMN trafficking and NETosis. Thus, MK as well as NETs may represent novel therapeutic targets for the treatment of cardiac inflammation. Copyright 2019 Weckbach et al.
SponsorsThis work was supported by the Deutsche Forschungsgemeinschaft (grant SFB 914, project A02 to B. Walzog, B02 to S. Massberg, and Z03 to B. Walzog; DFG KL 595/2-3 to K. Klingel), the FöFoLe (L.T. Weckbach and U. Grabmaier) and the LMU Excellence program of the Ludwig-Maximilians-University Munich (L.T. Weckbach and U. Grabmaier), the Deutsche Gesellschaft für Kardiologie (U. Grabmaier), and the National Institutes of Health (grants F31 CA19603301 to N. Sorrelle and R35 HL125743 to D.K. Strickland).
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85060935059&doi=10.1084%2fjem.20181102&partnerID=40&md5=3d286afe1089e456b4186fd4d29c3341; http://hdl.handle.net/10713/10689
- The cytokine midkine supports neutrophil trafficking during acute inflammation by promoting adhesion via β2 integrins (CD11/CD18).
- Authors: Weckbach LT, Gola A, Winkelmann M, Jakob SM, Groesser L, Borgolte J, Pogoda F, Pick R, Pruenster M, Müller-Höcker J, Deindl E, Sperandio M, Walzog B
- Issue date: 2014 Mar 20
- GM-CSF promotes inflammatory dendritic cell formation but does not contribute to disease progression in experimental autoimmune myocarditis.
- Authors: Blyszczuk P, Behnke S, Lüscher TF, Eriksson U, Kania G
- Issue date: 2013 Apr
- Endothelin receptor antagonist exacerbates autoimmune myocarditis in mice.
- Authors: Tajiri K, Sakai S, Kimura T, Machino-Ohtsuka T, Murakoshi N, Xu D, Wang Z, Sato A, Miyauchi T, Aonuma K
- Issue date: 2014 Nov 24
- Oleanolic acid modulates the immune-inflammatory response in mice with experimental autoimmune myocarditis and protects from cardiac injury. Therapeutic implications for the human disease.
- Authors: Martín R, Cordova C, San Román JA, Gutierrez B, Cachofeiro V, Nieto ML
- Issue date: 2014 Jul
- Regulation of inflammation and myocardial fibrosis in experimental autoimmune myocarditis.
- Authors: Watanabe K, Sukumaran V, Veeraveedu PT, Thandavarayan RA, Gurusamy N, Ma M, Arozal W, Sari FR, Lakshmanan AP, Arumugam S, Soetikno V, Rajavel V, Suzuki K
- Issue date: 2011 Jun