Induction of atrial fibrillation by neutrophils critically depends on CD11b/CD18 integrins
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Induction of atrial fibrillation by neutrophils critically depends on CD11b/CD18 integrins. / Friedrichs, Kai; Adam, Matti; Remane, Lisa; Mollenhauer, Martin; Rudolph, Volker; Rudolph, Tanja K; Andrié, René P; Stöckigt, Florian; Schrickel, Jan W; Ravekes, Thorben; Deuschl, Florian; Nickenig, Georg; Willems, Stephan; Baldus, Stephan; Klinke, Anna.
In: PLOS ONE, Vol. 9, No. 2, 2014, p. e89307.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Induction of atrial fibrillation by neutrophils critically depends on CD11b/CD18 integrins
AU - Friedrichs, Kai
AU - Adam, Matti
AU - Remane, Lisa
AU - Mollenhauer, Martin
AU - Rudolph, Volker
AU - Rudolph, Tanja K
AU - Andrié, René P
AU - Stöckigt, Florian
AU - Schrickel, Jan W
AU - Ravekes, Thorben
AU - Deuschl, Florian
AU - Nickenig, Georg
AU - Willems, Stephan
AU - Baldus, Stephan
AU - Klinke, Anna
PY - 2014
Y1 - 2014
N2 - BACKGROUND: Recent observational clinical and ex-vivo studies suggest that inflammation and in particular leukocyte activation predisposes to atrial fibrillation (AF). However, whether local binding and extravasation of leukocytes into atrial myocardium is an essential prerequisite for the initiation and propagation of AF remains elusive. Here we investigated the role of atrial CD11b/CD18 mediated infiltration of polymorphonuclear neutrophils (PMN) for the susceptibility to AF.METHODS AND RESULTS: C57bl/6J wildtype (WT) and CD11b/CD18 knock-out (CD11b(-/-)) mice were treated for 14 days with subcutaneous infusion of angiotensin II (Ang II), a known stimulus for PMN activation. Atria of Ang II-treated WT mice were characterized by increased PMN infiltration assessed in immunohistochemically stained sections. In contrast, atrial sections of CD11b(-/-) mice lacked a significant increase in PMN infiltration upon Ang II infusion. PMN infiltration was accompanied by profoundly enhanced atrial fibrosis in Ang II treated WT as compared to CD11b(-/-) mice. Upon in-vivo electrophysiological investigation, Ang II treatment significantly elevated the susceptibility for AF in WT mice if compared to vehicle treated animals given an increased number and increased duration of AF episodes. In contrast, animals deficient of CD11b/CD18 were entirely protected from AF induction. Likewise, epicardial activation mapping revealed decreased electrical conduction velocity in atria of Ang II treated WT mice, which was preserved in CD11b(-/-) mice. In addition, atrial PMN infiltration was enhanced in atrial appendage sections of patients with persistent AF as compared to patients without AF.CONCLUSIONS: The current data critically link CD11b-integrin mediated atrial PMN infiltration to the formation of fibrosis, which promotes the initiation and propagation of AF. These findings not only reveal a mechanistic role of leukocytes in AF but also point towards a potential novel avenue of treatment in AF.
AB - BACKGROUND: Recent observational clinical and ex-vivo studies suggest that inflammation and in particular leukocyte activation predisposes to atrial fibrillation (AF). However, whether local binding and extravasation of leukocytes into atrial myocardium is an essential prerequisite for the initiation and propagation of AF remains elusive. Here we investigated the role of atrial CD11b/CD18 mediated infiltration of polymorphonuclear neutrophils (PMN) for the susceptibility to AF.METHODS AND RESULTS: C57bl/6J wildtype (WT) and CD11b/CD18 knock-out (CD11b(-/-)) mice were treated for 14 days with subcutaneous infusion of angiotensin II (Ang II), a known stimulus for PMN activation. Atria of Ang II-treated WT mice were characterized by increased PMN infiltration assessed in immunohistochemically stained sections. In contrast, atrial sections of CD11b(-/-) mice lacked a significant increase in PMN infiltration upon Ang II infusion. PMN infiltration was accompanied by profoundly enhanced atrial fibrosis in Ang II treated WT as compared to CD11b(-/-) mice. Upon in-vivo electrophysiological investigation, Ang II treatment significantly elevated the susceptibility for AF in WT mice if compared to vehicle treated animals given an increased number and increased duration of AF episodes. In contrast, animals deficient of CD11b/CD18 were entirely protected from AF induction. Likewise, epicardial activation mapping revealed decreased electrical conduction velocity in atria of Ang II treated WT mice, which was preserved in CD11b(-/-) mice. In addition, atrial PMN infiltration was enhanced in atrial appendage sections of patients with persistent AF as compared to patients without AF.CONCLUSIONS: The current data critically link CD11b-integrin mediated atrial PMN infiltration to the formation of fibrosis, which promotes the initiation and propagation of AF. These findings not only reveal a mechanistic role of leukocytes in AF but also point towards a potential novel avenue of treatment in AF.
KW - Analysis of Variance
KW - Angiotensin II/administration & dosage
KW - Animals
KW - Atrial Fibrillation/etiology
KW - CD11b Antigen/genetics
KW - CD18 Antigens/genetics
KW - Electrophysiologic Techniques, Cardiac/methods
KW - Fluorescent Antibody Technique
KW - Heart Atria/metabolism
KW - Immunoblotting
KW - Immunohistochemistry
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Neutrophils/drug effects
U2 - 10.1371/journal.pone.0089307
DO - 10.1371/journal.pone.0089307
M3 - SCORING: Journal article
C2 - 24558493
VL - 9
SP - e89307
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 2
ER -
