Basophils balance healing after myocardial infarction via IL-4/IL-13

被引:61
作者
Sicklinger, Florian [1 ,2 ]
Meyer, Ingmar Soren [1 ,2 ]
Li, Xue [1 ,2 ]
Radtke, Daniel [3 ,4 ]
Dicks, Severin [5 ,6 ,7 ]
Kornadt, Moritz P. [1 ,2 ]
Mertens, Christina [8 ]
Meier, Julia K. [9 ]
Lavine, Kory J. [10 ]
Zhang, Yunhang [1 ,2 ]
Kuhn, Tim Christian [1 ,2 ]
Terzer, Tobias [11 ]
Patel, Jyoti [1 ,2 ]
Boerries, Melanie [5 ,6 ,12 ]
Schramm, Gabriele [13 ,14 ]
Frey, Norbert [1 ,2 ]
Katus, Hugo A. [1 ,2 ]
Voehringer, David [3 ,4 ]
Leuschner, Florian [1 ,2 ]
机构
[1] Univ Hosp Heidelberg, Dept Cardiol, Neuenheimer Feld 410, D-69120 Heidelberg, Germany
[2] German Ctr Cardiovasc Res DZHK, Partner Site Heidelberg, Heidelberg, Germany
[3] Univ Hosp Erlangen, Dept Infect Biol, Erlangen, Germany
[4] Friedrich Alexander Univ Erlangen Nuremberg FAU, Erlangen, Germany
[5] Univ Freiburg, Inst Med Bioinformat & Syst Med, Med Ctr, Freiburg, Germany
[6] Univ Freiburg, Fac Med, Freiburg, Germany
[7] Albert Ludwig Univ, Fac Biol, Freiburg, Germany
[8] Heidelberg Univ, Dept Pediat Hematol Oncol & Immunol, Heidelberg, Germany
[9] Goethe Univ Frankfurt, Fac Med, Inst Biochem 1, Frankfurt, Germany
[10] Washington Univ, Dept Med, St Louis, MO USA
[11] German Canc Res Ctr, Div Biostat, Heidelberg, Germany
[12] DKFZ, German Canc Consortium DKTK, Partner Site Freiburg, Freiburg, Germany
[13] Airway Res Ctr North, Expt Pneumol, Res Ctr Borstel, Borstel, Germany
[14] German Ctr Lung Res DZL, Borstel, Germany
关键词
HEART FUNCTION; MANSONI EGGS; MAST-CELLS; IN-VIVO; IPSE/ALPHA-1; MACROPHAGES; REPAIR; ROLES; INFLAMMATION; ACTIVATION;
D O I
10.1172/JCI136778
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent remodeling. Here, we show that basophil granulocytes infiltrated infarcted murine hearts, with a peak occurring between days 3 and 7. Antibody-mediated and genetic depletion of basophils deteriorated cardiac function and resulted in enhanced scar thinning after MI. Mechanistically, we found that basophil depletion was associated with a shift from reparative Ly6C(lo) macrophages toward increased numbers of inflammatory Ly6C(hi) monocytes in the infarcted myocardium. Restoration of basophils in basophil-deficient mice by adoptive transfer reversed this proinflammatory phenotype. Cellular alterations in the absence of basophils were accompanied by lower cardiac levels of IL-4 and IL-13, two major cytokines secreted by basophils. Mice with basophil-specific IL-4/IL-13 deficiency exhibited a similarly altered myeloid response with an increased fraction of Ly6C(hi) monocytes and aggravated cardiac function after MI. In contrast, IL-4 induction in basophils via administration of the glycoprotein IPSE/alpha-1 led to improved post-MI healing. These results in mice were corroborated by the finding that initially low counts of blood basophils in patients with acute MI were associated with a worse cardiac outcome after 1 year, characterized by a larger scar size. In conclusion, we show that basophils promoted tissue repair after MI by increasing cardiac IL-4 and IL-13 levels.
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页数:13
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