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@ARTICLE{Krammer:255141,
      author       = {Krammer, Christine and Yang, Bishan and Reichl, Sabrina and
                      Besson-Girard, Simon and Ji, Hao and Bolini, Verena and
                      Schulte, Corinna and Noels, Heidi and Schlepckow, Kai and
                      Jocher, Georg and Werner, Georg and Willem, Michael and El
                      Bounkari, Omar and Kapurniotu, Aphrodite and Gökce, Ozgun
                      and Weber, Christian and Mohanta, Sarajo and Bernhagen,
                      Jürgen},
      title        = {{P}athways linking aging and atheroprotection in
                      {M}if-deficient atherosclerotic mice.},
      journal      = {The FASEB journal},
      volume       = {37},
      number       = {3},
      issn         = {0892-6638},
      address      = {Hoboken, NJ},
      publisher    = {Wiley},
      reportid     = {DZNE-2023-00260},
      pages        = {e22752},
      year         = {2023},
      abstract     = {Atherosclerosis is a chronic inflammatory condition of our
                      arteries and the main underlying pathology of myocardial
                      infarction and stroke. The pathogenesis is age-dependent,
                      but the links between disease progression, age, and
                      atherogenic cytokines and chemokines are incompletely
                      understood. Here, we studied the chemokine-like inflammatory
                      cytokine macrophage migration inhibitory factor (MIF) in
                      atherogenic Apoe-/- mice across different stages of aging
                      and cholesterol-rich high-fat diet (HFD). MIF promotes
                      atherosclerosis by mediating leukocyte recruitment, lesional
                      inflammation, and suppressing atheroprotective B cells.
                      However, links between MIF and advanced atherosclerosis
                      across aging have not been systematically explored. We
                      compared effects of global Mif-gene deficiency in 30-, 42-,
                      and 48-week-old Apoe-/- mice on HFD for 24, 36, or 42 weeks,
                      respectively, and in 52-week-old mice on a 6-week HFD.
                      Mif-deficient mice exhibited reduced atherosclerotic lesions
                      in the 30/24- and 42/36-week-old groups, but
                      atheroprotection, which in the applied Apoe-/- model was
                      limited to lesions in the brachiocephalic artery and
                      abdominal aorta, was not detected in the 48/42- and
                      52/6-week-old groups. This suggested that atheroprotection
                      afforded by global Mif-gene deletion differs across aging
                      stages and atherogenic diet duration. To characterize this
                      phenotype and study the underlying mechanisms, we determined
                      immune cells in the periphery and vascular lesions, obtained
                      a multiplex cytokine/chemokine profile, and compared the
                      transcriptome between the age-related phenotypes. We found
                      that Mif deficiency promotes lesional macrophage and T-cell
                      counts in younger but not aged mice, with subgroup analysis
                      pointing toward a role for Trem2+ macrophages. The
                      transcriptomic analysis identified pronounced MIF- and
                      aging-dependent changes in pathways predominantly related to
                      lipid synthesis and metabolism, lipid storage, and brown fat
                      cell differentiation, as well as immunity, and
                      atherosclerosis-relevant enriched genes such as Plin1, Ldlr,
                      Cpne7, or Il34, hinting toward effects on lesional lipids,
                      foamy macrophages, and immune cells. Moreover, Mif-deficient
                      aged mice exhibited a distinct plasma cytokine/chemokine
                      signature consistent with the notion that mediators known to
                      drive inflamm'aging are either not downregulated or even
                      upregulated in Mif-deficient aged mice compared with the
                      corresponding younger ones. Lastly, Mif deficiency favored
                      formation of lymphocyte-rich peri-adventitial leukocyte
                      clusters. While the causative contributions of these
                      mechanistic pillars and their interplay will be subject to
                      future scrutiny, our study suggests that atheroprotection
                      due to global Mif-gene deficiency in atherogenic Apoe-/-
                      mice is reduced upon advanced aging and identifies
                      previously unrecognized cellular and molecular targets that
                      could explain this phenotype shift. These observations
                      enhance our understanding of inflamm'aging and MIF pathways
                      in atherosclerosis and may have implications for
                      translational MIF-directed strategies.},
      keywords     = {Animals / Mice / Macrophage Migration-Inhibitory Factors:
                      genetics / Macrophage Migration-Inhibitory Factors:
                      metabolism / Atherosclerosis: metabolism / Chemokines /
                      Aging / Apolipoproteins E: metabolism / Mice, Knockout /
                      Mice, Inbred C57BL / Plaque, Atherosclerotic / Membrane
                      Glycoproteins / Receptors, Immunologic / MIF (Other) / aging
                      (Other) / artery tertiary lymphoid organ (Other) /
                      atherosclerosis (Other) / atypical chemokines (Other) /
                      chemokines (Other) / Macrophage Migration-Inhibitory Factors
                      (NLM Chemicals) / Chemokines (NLM Chemicals) /
                      Apolipoproteins E (NLM Chemicals) / Trem2 protein, mouse
                      (NLM Chemicals) / Membrane Glycoproteins (NLM Chemicals) /
                      Receptors, Immunologic (NLM Chemicals)},
      cin          = {AG Haass / AG Lichtenthaler},
      ddc          = {570},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)1110006},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36794636},
      doi          = {10.1096/fj.202200056R},
      url          = {https://pub.dzne.de/record/255141},
}