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@ARTICLE{Meyer:128102,
      author       = {I. S. Meyer and A. Jungmann and C. Dieterich and M. Zhang
                      and F. Lasitschka and S. Werkmeister and J. Haas and O. J.
                      Müller and M. Boutros$^*$ and M. Nahrendorf and H. A. Katus
                      and S. E. Hardt and F. Leuschner},
      title        = {{T}he cardiac microenvironment uses non-canonical {WNT}
                      signaling to activate monocytes after myocardial
                      infarction.},
      journal      = {EMBO molecular medicine},
      volume       = {9},
      number       = {9},
      issn         = {1757-4684},
      address      = {Weinheim},
      publisher    = {Wiley-VCH},
      reportid     = {DKFZ-2017-04124},
      pages        = {1279 - 1293},
      year         = {2017},
      abstract     = {A disturbed inflammatory response following myocardial
                      infarction (MI) is associated with poor prognosis and
                      increased tissue damage. Monocytes are key players in
                      healing after MI, but little is known about the role of the
                      cardiac niche in monocyte activation. This study
                      investigated microenvironment-dependent changes in
                      inflammatory monocytes after MI RNA sequencing analysis of
                      murine Ly6C(high) monocytes on day 3 after MI revealed
                      differential regulation depending on location. Notably, the
                      local environment strongly impacted components of the WNT
                      signaling cascade. Analysis of WNT modulators revealed a
                      strong upregulation of WNT Inhibitory Factor 1 (WIF1) in
                      cardiomyocytes-but not fibroblasts or endothelial cells-upon
                      hypoxia. Compared to wild-type (WT) littermates, WIF1
                      knockout mice showed severe adverse remodeling marked by
                      increased scar size and reduced ejection fraction 4 weeks
                      after MI While FACS analysis on day 1 after MI revealed no
                      differences in neutrophil numbers, the hearts of WIF1
                      knockouts contained significantly more inflammatory
                      monocytes than hearts from WT animals. Next, we induced
                      AAV-mediated cardiomyocyte-specific WIF1 overexpression,
                      which attenuated the monocyte response and improved cardiac
                      function after MI, as compared to control-AAV-treated
                      animals. Finally, WIF1 overexpression in isolated
                      cardiomyocytes limited the activation of non-canonical WNT
                      signaling and led to reduced IL-1β and IL-6 expression in
                      monocytes/macrophages. Taken together, we investigated the
                      cardiac microenvironment's interaction with recruited
                      monocytes after MI and identified a novel mechanism of
                      monocyte activation. The local initiation of non-canonical
                      WNT signaling shifts the accumulating myeloid cells toward a
                      pro-inflammatory state and impacts healing after myocardial
                      infarction.},
      cin          = {B110},
      ddc          = {610},
      cid          = {I:(DE-He78)B110-20160331},
      pnm          = {322 - Genetics and Pathophysiology (POF3-322)},
      pid          = {G:(DE-HGF)POF3-322},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28774883},
      pmc          = {pmc:PMC5582413},
      doi          = {10.15252/emmm.201707565},
      url          = {https://inrepo02.dkfz.de/record/128102},
}