Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets.

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We thank D. Mangelsdorf (University of Texas Southwestern Medical Center) for LXRα- and LXRβ-sufficient wild-type (Nr1h3+/+Nr1h2+/+) mice, LXRα-deficient (Nr1h3−/−) mice, LXRβ-deficient (Nr1h2−/−) mice and LXR-deficient (Nr1h3−/−Nr1h2−/−) mice; the Institut Clinique de la Souris for Nr1h3fl/fl mice; D. Kioussis (Medical Research Council) and S. Gonzalez (Centro Nacional de Investigaciones Cardiovasculares) for Vav-Cre mice; S. Gordon and M. Stacey (University of Oxford) for antibody to F4/80 (anti-F4/80) and anti-CD169; G. Randolph (Washington University St. Louis) for discussions and anti-TREML4 from the R. Steinman laboratory (Rockefeller University); M. Kosco-Vilbois (NovImmune) for anti-FDC-M1 and anti-FDC-M2; J. Collins and T. Willson (GlaxoSmithKline) for the synthetic ligands of LXR (GW3965) and retinoid X receptor (LG268); N. Ruddle, C. Glass, N. Spann, A. Chawla, G. Lemke, D. Hume, L. Hedrick, A. Lazarus and L. Bosca for comments; and Servicio Microscopia Electronica (University of Las Palmas de Gran Canaria) for electron microscopy. Supported by the Spanish Ministry of Research and Innovation (SAF2008-00057 to A.C.), the Ministry of Economy and Competitiveness (SAF2011-29244 to A.C. and SAF2009-11037 to A.H.), Framework Programme 7 of the European Union (International Reintegration Grant IRG246655 to A.H.), the Howard Hughes Medical Institute (P.T.), the US National Institutes of Health (HL-066088 and HL-030568 to P.T.), Subprograma Ramón y Cajal (RYC-2007-00697 to A.H.), Formación de Personal Investigador (BES-2010-032828 to M.C.-A. and BES-2009-012191 to I.H.H.) and Universidad Las Palmas de Gran Canaria (J.V.d.l.R.).

Author information

Author notes

    • Noelia A-Gonzalez
    • , Jose A Guillen
    • , Germán Gallardo
    •  & Mercedes Diaz

    These authors contributed equally to this work.


  1. Instituto de Investigaciones Biomédicas “Alberto Sols” de Madrid, Consejo Superior de Investigaciones Cientificas–Universidad Autonóma de Madrid, Madrid, Spain.

    • Noelia A-Gonzalez
    • , Jose A Guillen
    • , Mercedes Diaz
    • , Irene H Hernandez
    • , Susana Beceiro
    •  & Antonio Castrillo
  2. Unidad Asociada de Biomedicina, Instituto de Investigaciones Biomédicas “Alberto Sols” de Madrid, Consejo Superior de Investigaciones Cientificas–Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.

    • Noelia A-Gonzalez
    • , Jose A Guillen
    • , Germán Gallardo
    • , Mercedes Diaz
    • , Juan V de la Rosa
    • , Irene H Hernandez
    • , Felix Lopez
    • , Carlos Tabraue
    • , Susana Beceiro
    •  & Antonio Castrillo
  3. Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.

    • Noelia A-Gonzalez
    • , Maria Casanova-Acebes
    •  & Andres Hidalgo
  4. Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California Los Angeles, California, USA.

    • Cynthia Hong
    •  & Peter Tontonoz
  5. Servicio de Oncología Radioterápica, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas, Spain.

    • Pedro C Lara
  6. Servicio de Patología, Hospital Universitario Materno-Infantil de Las Palmas, Las Palmas, Spain.

    • Miguel Andujar
  7. Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

    • Satoko Arai
    •  & Toru Miyazaki
  8. Departments of Medicine and Pharmacology, University of Texas Health Science Center, San Antonio, Texas, USA.

    • Senlin Li
  9. South Texas Veterans Health Care System, San Antonio, Texas, USA.

    • Senlin Li
  10. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.

    • Angel L Corbi


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N.A.-G., J.A.G., G.G. and M.D. designed and did experiments and analyzed data; J.V.d.l.R., I.H.H., M.C.-A., F.L., C.T. and S.B. did experiments; C.H., P.C.L., M.A., S.A., T.M., S.L., A.L.C., P.T. and A.H. provided reagents and intellectual input and analyzed or interpreted data; N.A.-G. and A.H. contributed to the writing of the manuscript; and A.C. supervised the project, designed and did experiments, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Antonio Castrillo.

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