title: M1 macrophages act as LTβR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis.
abstract: OBJECTIVE
  The goal of this study was to characterize the role of inflammatory macrophages in the induction of the vascular smooth muscle cell (VSMC)-mediated formation of aortic tertiary lymphoid organs (TLOs).
  
  
  RESULTS
  Mouse bone marrow-derived M1 macrophages acted as lymphoid tissue inducer cells. Indeed, they expressed high levels of tumour necrosis factor (TNF)-α and membrane-bound lymphotoxin (LT)-α, two inducing cytokines that triggered expression of the chemokines CCL19, CCL20, and CXCL16, as did M1 supernatant. The blockade of LTβR signalling with LTβR-Ig had no effect, whereas that of TNFR1/2 signalling reduced chemokine expression by VSMCs in both wild-type (WT) and LTβR KO mice, demonstrating that LTβR signalling is dispensable for the M1-inducing effect. This effect was corroborated by the development of TLOs observed in LTβR KO->apolipoprotein E knockout (ApoE KO) aortic segments after orthotopic transplantation. Furthermore, treatment of ApoE KO mice with anti-TNF-α antibody decreased the number and incidence of aortic TLOs. Finally, lymphoid nodules composed of T and B cells formed in in vivo-implanted scaffolds seeded with VSMCs previously stimulated ex vivo by M1-conditioned medium.
  
  
  CONCLUSIONS
  These results are the first to identify M1 macrophages as inducer cells that trigger the expression of chemokines by VSMCs independently of LTβR signalling. We propose that the dialogue between macrophages and VSMCs-established across the vascular wall-contributes to the formation of aortic TLOs.
authors.affiliation: Unité 698, Institut National de la Santé et de la Recherche Médicale, Hôpital Xavier Bichat, Paris, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Guedj
authors.forename: Jamila
authors.initials: J
authors.lastname: Khallou-Laschet
authors.forename: Marc
authors.initials: M
authors.lastname: Clement
authors.forename: Marion
authors.initials: M
authors.lastname: Morvan
authors.forename: Anh-Thu
authors.initials: AT
authors.lastname: Gaston
authors.forename: Giulia
authors.initials: G
authors.lastname: Fornasa
authors.forename: Jianping
authors.initials: J
authors.lastname: Dai
authors.forename: Marianne
authors.initials: M
authors.lastname: Gervais-Taurel
authors.forename: Gerard
authors.initials: G
authors.lastname: Eberl
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Caligiuri
authors.forename: Antonino
authors.initials: A
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000166:cytology / Q000378:metabolism*; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D053259:Lymphotoxin beta Receptor; D014409:Tumor Necrosis Factor-alpha
keywords: Atherosclerosis; Chemokine; Lymphocyte; Macrophage; Smooth muscle cell