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.).
The authors declare no competing financial interests.
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A-Gonzalez, N., Guillen, J., Gallardo, G. et al. The nuclear receptor LXRα controls the functional specialization of splenic macrophages. Nat Immunol 14, 831–839 (2013). https://doi.org/10.1038/ni.2622
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