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• W2949761254 abstract "•Ccl19-cre-mediated RANKL deletion in LTOs and MRCs inactivates LECs and leads to SM loss•Development and repair of the SM network fails in mice with RANK-deficient LECs•Cd169-cre Rankfl/fl mice reveal that SSMs but not MSMs require direct RANK signaling•The stromal RANK-RANKL axis governs the SM-mediated antiviral immune response Tissue-resident macrophages are receptive to specific signals concentrated in cellular niches that direct their cell differentiation and maintenance genetic programs. Here, we found that deficiency of the cytokine RANKL in lymphoid tissue organizers and marginal reticular stromal cells of lymph nodes resulted in the loss of the CD169+ sinusoidal macrophages (SMs) comprising the subcapsular and the medullary subtypes. Subcapsular SM differentiation was impaired in mice with targeted RANK deficiency in SMs. Temporally controlled RANK removal in lymphatic endothelial cells (LECs) revealed that lymphatic RANK activation during embryogenesis and shortly after birth was required for the differentiation of both SM subtypes. Moreover, RANK expression by LECs was necessary for SM restoration after inflammation-induced cell loss. Thus, cooperation between mesenchymal cells and LECs shapes a niche environment that supports SM differentiation and reconstitution after inflammation. Tissue-resident macrophages are receptive to specific signals concentrated in cellular niches that direct their cell differentiation and maintenance genetic programs. Here, we found that deficiency of the cytokine RANKL in lymphoid tissue organizers and marginal reticular stromal cells of lymph nodes resulted in the loss of the CD169+ sinusoidal macrophages (SMs) comprising the subcapsular and the medullary subtypes. Subcapsular SM differentiation was impaired in mice with targeted RANK deficiency in SMs. Temporally controlled RANK removal in lymphatic endothelial cells (LECs) revealed that lymphatic RANK activation during embryogenesis and shortly after birth was required for the differentiation of both SM subtypes. Moreover, RANK expression by LECs was necessary for SM restoration after inflammation-induced cell loss. Thus, cooperation between mesenchymal cells and LECs shapes a niche environment that supports SM differentiation and reconstitution after inflammation. Lymphoid tissues comprise mesenchymal and endothelial stromal cells. They play a key role in the development of secondary lymphoid organs such as lymph nodes (LNs) (Onder and Ludewig, 2018Onder L. Ludewig B. A fresh view on lymph node organogenesis.Trends Immunol. 2018; 39: 775-787Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, van de Pavert and Mebius, 2010van de Pavert S.A. Mebius R.E. New insights into the development of lymphoid tissues.Nat. Rev. Immunol. 2010; 10: 664-674Crossref PubMed Scopus (442) Google Scholar) and function in the compartmentalization of B cell and T cell zones, antigen transport, and immune regulation (Buechler and Turley, 2018Buechler M.B. Turley S.J. A short field guide to fibroblast function in immunity.Semin. Immunol. 2018; 35: 48-58Crossref PubMed Scopus (63) Google Scholar). Recently, an increasing diversity of mesenchymal stromal cells has emerged (Huang et al., 2018Huang H.Y. Rivas-Caicedo A. Renevey F. Cannelle H. Peranzoni E. Scarpellino L. Hardie D.L. Pommier A. Schaeuble K. Favre S. et al.Identification of a new subset of lymph node stromal cells involved in regulating plasma cell homeostasis.Proc. Natl. Acad. Sci. USA. 2018; 115: E6826-E6835Crossref PubMed Scopus (60) Google Scholar, Rodda et al., 2018Rodda L.B. Lu E. Bennett M.L. Sokol C.L. Wang X. Luther S.A. Barres B.A. Luster A.D. Ye C.J. Cyster J.G. Single-Cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028.e6Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, Takeuchi et al., 2018Takeuchi A. Ozawa M. Kanda Y. Kozai M. Ohigashi I. Kurosawa Y. Rahman M.A. Kawamura T. Shichida Y. Umemoto E. et al.A distinct subset of fibroblastic stromal cells constitutes the cortex-medulla boundary subcompartment of the lymph node.Front. Immunol. 2018; 9: 2196Crossref PubMed Scopus (19) Google Scholar), among which the marginal reticular cells (MRCs). They reside in the LN marginal area between the subcapsular sinus and the B cell follicles and are characterized by the expression of the tumor necrosis factor superfamily (TNFSF) member receptor activator of nuclear factor kappa-Β ligand (RANKL) (TNFSF11) (Katakai et al., 2008Katakai T. Suto H. Sugai M. Gonda H. Togawa A. Suematsu S. Ebisuno Y. Katagiri K. Kinashi T. Shimizu A. Organizer-like reticular stromal cell layer common to adult secondary lymphoid organs.J. Immunol. 2008; 181: 6189-6200Crossref PubMed Scopus (192) Google Scholar, Rodda et al., 2018Rodda L.B. Lu E. Bennett M.L. Sokol C.L. Wang X. Luther S.A. Barres B.A. Luster A.D. Ye C.J. Cyster J.G. Single-Cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028.e6Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). RANKL is known for the differentiation of osteoclasts, specialized bone-resorbing macrophages (Dougall et al., 1999Dougall W.C. Glaccum M. Charrier K. Rohrbach K. Brasel K. De Smedt T. Daro E. Smith J. Tometsko M.E. Maliszewski C.R. et al.RANK is essential for osteoclast and lymph node development.Genes Dev. 1999; 13: 2412-2424Crossref PubMed Scopus (1202) Google Scholar, Kong et al., 1999Kong Y.Y. Yoshida H. Sarosi I. Tan H.L. Timms E. Capparelli C. Morony S. Oliveira-dos-Santos A.J. Van G. Itie A. et al.OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis.Nature. 1999; 397: 315-323Crossref PubMed Scopus (2863) Google Scholar, Walsh and Choi, 2014Walsh M.C. Choi Y. Biology of the RANKL-RANK-OPG System in immunity, bone, and beyond.Front. Immunol. 2014; 5: 511Crossref PubMed Scopus (416) Google Scholar), but is also required for LN organogenesis given that mice deficient for RANKL or its signaling receptor, receptor activator of NF-κB (RANK) (TNFRSF11a), lack all LNs (Dougall et al., 1999Dougall W.C. Glaccum M. Charrier K. Rohrbach K. Brasel K. De Smedt T. Daro E. Smith J. Tometsko M.E. Maliszewski C.R. et al.RANK is essential for osteoclast and lymph node development.Genes Dev. 1999; 13: 2412-2424Crossref PubMed Scopus (1202) Google Scholar, Kim et al., 2000Kim D. Mebius R.E. MacMicking J.D. Jung S. Cupedo T. Castellanos Y. Rho J. Wong B.R. Josien R. Kim N. et al.Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE.J. Exp. Med. 2000; 192: 1467-1478Crossref PubMed Scopus (231) Google Scholar, Kong et al., 1999Kong Y.Y. Yoshida H. Sarosi I. Tan H.L. Timms E. Capparelli C. Morony S. Oliveira-dos-Santos A.J. Van G. Itie A. et al.OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis.Nature. 1999; 397: 315-323Crossref PubMed Scopus (2863) Google Scholar). In the embryonic LN anlagen, RANKL is expressed by the stromal lymphoid tissue organizers (LTOs) and lymphoid tissue inducer (LTi) cells (Cupedo et al., 2004Cupedo T. Vondenhoff M.F. Heeregrave E.J. De Weerd A.E. Jansen W. Jackson D.G. Kraal G. Mebius R.E. Presumptive lymph node organizers are differentially represented in developing mesenteric and peripheral nodes.J. Immunol. 2004; 173: 2968-2975Crossref PubMed Scopus (101) Google Scholar, Sugiyama et al., 2012Sugiyama M. Nakato G. Jinnohara T. Akiba H. Okumura K. Ohno H. Yoshida H. Expression pattern changes and function of RANKL during mouse lymph node microarchitecture development.Int. Immunol. 2012; 24: 369-378Crossref PubMed Scopus (21) Google Scholar), and it has recently been shown that RANK expression by lymphatic endothelial cells (LECs) is necessary for LN organogenesis (Onder et al., 2017Onder L. Mörbe U. Pikor N. Novkovic M. Cheng H.W. Hehlgans T. Pfeffer K. Becher B. Waisman A. Rülicke T. et al.Lymphatic endothelial cells control initiation of lymph node organogenesis.Immunity. 2017; 47: 80-92.e4Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). However, the function of stromal RANKL in LNs remains incompletely understood. We have recently observed that stromal RANKL activates LECs to express integrin alpha 2b (ITGA2b), suggesting that a cross-talk between these two cell types could affect immune function (Cordeiro et al., 2016Cordeiro O.G. Chypre M. Brouard N. Rauber S. Alloush F. Romera-Hernandez M. Bénézech C. Li Z. Eckly A. Coles M.C. et al.Integrin-Alpha IIb identifies murine lymph node lymphatic endothelial cells responsive to RANKL.PLoS ONE. 2016; 11: e0151848Crossref PubMed Scopus (27) Google Scholar). Macrophages that line the lymphatic sinuses of LNs comprise the CD169+ subcapsular sinus macrophages (SSMs), localized between the B cell follicles and the subcapsular sinus, and the CD169+SIGN-R1+F4/80+ medullary sinus macrophages (MSMs) associated with the medullary lymphatics. Both populations play an important role in the initiation and the regulation of innate and adaptive immunity (Gray and Cyster, 2012Gray E.E. Cyster J.G. Lymph node macrophages.J. Innate Immun. 2012; 4: 424-436Crossref PubMed Scopus (172) Google Scholar). In response to viral pathogens, SSMs produce type I interferon (IFN-I) that protects neighboring cells (Iannacone et al., 2010Iannacone M. Moseman E.A. Tonti E. Bosurgi L. Junt T. Henrickson S.E. Whelan S.P. Guidotti L.G. von Andrian U.H. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus.Nature. 2010; 465: 1079-1083Crossref PubMed Scopus (251) Google Scholar, Moseman et al., 2012Moseman E.A. Iannacone M. Bosurgi L. Tonti E. Chevrier N. Tumanov A. Fu Y.X. Hacohen N. von Andrian U.H. B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity.Immunity. 2012; 36: 415-426Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar) or activate the inflammasome that fuels the immune response (Sagoo et al., 2016Sagoo P. Garcia Z. Breart B. Lemaître F. Michonneau D. Albert M.L. Levy Y. Bousso P. In vivo imaging of inflammasome activation reveals a subcapsular macrophage burst response that mobilizes innate and adaptive immunity.Nat. Med. 2016; 22: 64-71Crossref PubMed Scopus (83) Google Scholar). SSMs also transfer lymph-borne antigens to B cells that relay it to the follicular dendritic cells (FDCs) for an efficient secondary immune response (Carrasco and Batista, 2007Carrasco Y.R. Batista F.D. B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node.Immunity. 2007; 27: 160-171Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar, Phan et al., 2007Phan T.G. Grigorova I. Okada T. Cyster J.G. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells.Nat. Immunol. 2007; 8: 992-1000Crossref PubMed Scopus (482) Google Scholar). MSMs also contribute to the immune response by the release of inflammatory mediators (Chatziandreou et al., 2017Chatziandreou N. Farsakoglu Y. Palomino-Segura M. D’Antuono R. Pizzagalli D.U. Sallusto F. Lukacs-Kornek V. Uguccioni M. Corti D. Turley S.J. et al.Macrophage death following influenza vaccination initiates the inflammatory response that promotes dendritic cell function in the draining lymph node.Cell Rep. 2017; 18: 2427-2440Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Tissue macrophages derive from yolk sac macrophages and fetal liver monocytes or, in the adult, from bone-marrow-derived precursors (Ginhoux and Guilliams, 2016Ginhoux F. Guilliams M. Tissue-resident macrophage ontogeny and homeostasis.Immunity. 2016; 44: 439-449Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar). Lineage-determining transcription factors provide a core macrophage development program, and tissue-derived signals oversee the final differentiation refinement (Lavin et al., 2015Lavin Y. Mortha A. Rahman A. Merad M. Regulation of macrophage development and function in peripheral tissues.Nat. Rev. Immunol. 2015; 15: 731-744Crossref PubMed Scopus (365) Google Scholar, T’Jonck et al., 2018T’Jonck W. Guilliams M. Bonnardel J. Niche signals and transcription factors involved in tissue-resident macrophage development.Cell. Immunol. 2018; 330: 43-53Crossref PubMed Scopus (87) Google Scholar). Macrophage precursors can receive secondary signals that are unique to each particular cell niche through cell-cell contacts and soluble factors (Guilliams and Scott, 2017Guilliams M. Scott C.L. Does niche competition determine the origin of tissue-resident macrophages?.Nat. Rev. Immunol. 2017; 17: 451-460Crossref PubMed Scopus (245) Google Scholar). It ensures that the macrophages are well adapted to their local environment. SMs require colony stimulating factor 1 receptor (CSF1R) signals (Witmer-Pack et al., 1993Witmer-Pack M.D. Hughes D.A. Schuler G. Lawson L. McWilliam A. Inaba K. Steinman R.M. Gordon S. Identification of macrophages and dendritic cells in the osteopetrotic (op/op) mouse.J. Cell Sci. 1993; 104: 1021-1029Crossref PubMed Google Scholar), but in addition, SSM differentiation is dependent on lymphotoxin (LT) αβ produced by the adjacent B cells (Moseman et al., 2012Moseman E.A. Iannacone M. Bosurgi L. Tonti E. Chevrier N. Tumanov A. Fu Y.X. Hacohen N. von Andrian U.H. B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity.Immunity. 2012; 36: 415-426Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, Phan et al., 2009Phan T.G. Green J.A. Gray E.E. Xu Y. Cyster J.G. Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation.Nat. Immunol. 2009; 10: 786-793Crossref PubMed Scopus (306) Google Scholar). Here, we examined the role of RANKL expressed by the mesenchymal LTO and MRC stromal cells in the LNs. We found that Ccl19 promoter-directed RANKL ablation in LTOs and MRCs did not affect LN organogenesis but resulted in the specific loss of SMs. Deficiency in RANK affected SSMs directly given that these cells were absent in Cd169-cre Rankfl/fl mice. However, deletion of RANK in LECs during mouse embryogenesis or in the first weeks after birth resulted in the loss of both SM subsets. RANK activation of LECs was also required for SM-network restoration after an inflammatory insult. Inactivation of RANK signaling in LECs correlated with the reduced presence of CD11b+ cells in embryos and adult mice, supporting a role for this axis in cell recruitment or retention. As a result, the absence of mesenchymal RANKL or lymphatic RANK compromised the immune response to a viral pathogen. Altogether, our findings show that this mesenchymal-endothelial cell interaction shapes a niche environment that is mandatory for SM differentiation during development and for reconstitution after inflammation. C-C motif chemokine ligand 19 (CCL19) is expressed in LTOs (Bénézech et al., 2010Bénézech C. White A. Mader E. Serre K. Parnell S. Pfeffer K. Ware C.F. Anderson G. Caamaño J.H. Ontogeny of stromal organizer cells during lymph node development.J. Immunol. 2010; 184: 4521-4530Crossref PubMed Scopus (93) Google Scholar, Chai et al., 2013Chai Q. Onder L. Scandella E. Gil-Cruz C. Perez-Shibayama C. Cupovic J. Danuser R. Sparwasser T. Luther S.A. Thiel V. et al.Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity.Immunity. 2013; 38: 1013-1024Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar) that are presumed to give rise to the MRCs, the main constitutive source of RANKL in the adult LNs (Katakai, 2012Katakai T. Marginal reticular cells: a stromal subset directly descended from the lymphoid tissue organizer.Front. Immunol. 2012; 3: 200-206Crossref PubMed Scopus (67) Google Scholar, Rodda et al., 2018Rodda L.B. Lu E. Bennett M.L. Sokol C.L. Wang X. Luther S.A. Barres B.A. Luster A.D. Ye C.J. Cyster J.G. Single-Cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity.Immunity. 2018; 48: 1014-1028.e6Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). Therefore, to address the function of stromal RANKL, we crossed Ranklfl/fl mice (Xiong et al., 2011Xiong J. Onal M. Jilka R.L. Weinstein R.S. Manolagas S.C. O’Brien C.A. Matrix-embedded cells control osteoclast formation.Nat. Med. 2011; 17: 1235-1241Crossref PubMed Scopus (962) Google Scholar) with mice expressing the cre recombinase under control of the Ccl19 promoter (Chai et al., 2013Chai Q. Onder L. Scandella E. Gil-Cruz C. Perez-Shibayama C. Cupovic J. Danuser R. Sparwasser T. Luther S.A. Thiel V. et al.Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity.Immunity. 2013; 38: 1013-1024Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Microscopic inspection of embryonic day (E) 17.5 inguinal LNs of Ccl19-cre Ranklfl/fl mice (denoted as RanklΔCcl19) revealed a markedly diminished expression of RANKL by the LTOs (Figure 1A). At this age, LTi cells express little RANKL (Sugiyama et al., 2012Sugiyama M. Nakato G. Jinnohara T. Akiba H. Okumura K. Ohno H. Yoshida H. Expression pattern changes and function of RANKL during mouse lymph node microarchitecture development.Int. Immunol. 2012; 24: 369-378Crossref PubMed Scopus (21) Google Scholar). LECs, identified by murine chloride channel calcium-activated 1 (mCLCA1) (Furuya et al., 2010Furuya M. Kirschbaum S.B. Paulovich A. Pauli B.U. Zhang H. Alexander J.S. Farr A.G. Ruddell A. Lymphatic endothelial murine chloride channel calcium-activated 1 is a ligand for leukocyte LFA-1 and Mac-1.J. Immunol. 2010; 185: 5769-5777Crossref PubMed Scopus (19) Google Scholar), and the presence of mature LTi cells expressing CD4 appeared normal. The mice developed all LNs with little alteration in cellularity and cell composition (Figures S1A and S1B), which is in contrast to unconditional RANKL-deficient mice that lack all LNs (Kong et al., 1999Kong Y.Y. Yoshida H. Sarosi I. Tan H.L. Timms E. Capparelli C. Morony S. Oliveira-dos-Santos A.J. Van G. Itie A. et al.OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis.Nature. 1999; 397: 315-323Crossref PubMed Scopus (2863) Google Scholar). In agreement with a direct lineage relationship between LTOs and MRCs (Takeuchi et al., 2018Takeuchi A. Ozawa M. Kanda Y. Kozai M. Ohigashi I. Kurosawa Y. Rahman M.A. Kawamura T. Shichida Y. Umemoto E. et al.A distinct subset of fibroblastic stromal cells constitutes the cortex-medulla boundary subcompartment of the lymph node.Front. Immunol. 2018; 9: 2196Crossref PubMed Scopus (19) Google Scholar), the expression of RANKL was no longer observed in MRCs of adult RanklΔCcl19 mice (Figure 1B). To determine whether the disappearance of RANKL altered MRC differentiation, we identified MRCs among the gp38+CD31− stromal fibroblastic reticular cells (FRCs) on the basis of the expression of mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) and vascular cell adhesion protein (VCAM-1) (Hoorweg et al., 2015Hoorweg K. Narang P. Li Z. Thuery A. Papazian N. Withers D.R. Coles M.C. Cupedo T. A stromal cell niche for human and mouse type 3 innate lymphoid cells.J. Immunol. 2015; 195: 4257-4263Crossref PubMed Scopus (35) Google Scholar, Katakai et al., 2008Katakai T. Suto H. Sugai M. Gonda H. Togawa A. Suematsu S. Ebisuno Y. Katagiri K. Kinashi T. Shimizu A. Organizer-like reticular stromal cell layer common to adult secondary lymphoid organs.J. Immunol. 2008; 181: 6189-6200Crossref PubMed Scopus (192) Google Scholar) (Figure 1C). The proportion of MRCs was not altered in the RANKL mutant mice (Figure 1D). Moreover, when RanklΔCcl19 mice were crossed with tdTomato reporter mice, red fluorescent stromal cells were found between the FDCs and the subcapsular sinus, indicative of correctly positioned MRCs (Figure S1C). TdTomato+ T-cell-zone-residing reticular cells (TRCs) were also observed, suggesting that the lack of RANKL has no effect on other stromal subsets. We determined Rankl gene expression by RT-qPCR in sorted MRCs and in the remaining stroma of RanklΔCcl19 and control Ranklfl/fl mice. Figure 1E shows that MRCs transcribed Rankl, and as expected, there was a clear reduction in the number of transcripts in MRCs from RanklΔCcl19 mice. Altogether, the chosen gene-targeting strategy established a reliable mouse model for Rankl deletion from the mesenchymal LN stromal cells. In light of the expression of RANK by the myeloid lineage in response to CSF-1 (Arai et al., 2012Arai A. Mizoguchi T. Harada S. Kobayashi Y. Nakamichi Y. Yasuda H. Penninger J.M. Yamada K. Udagawa N. Takahashi N. Fos plays an essential role in the upregulation of RANK expression in osteoclast precursors within the bone microenvironment.J. Cell Sci. 2012; 125: 2910-2917Crossref PubMed Scopus (80) Google Scholar), alongside its role in osteoclastogenesis (Dougall et al., 1999Dougall W.C. Glaccum M. Charrier K. Rohrbach K. Brasel K. De Smedt T. Daro E. Smith J. Tometsko M.E. Maliszewski C.R. et al.RANK is essential for osteoclast and lymph node development.Genes Dev. 1999; 13: 2412-2424Crossref PubMed Scopus (1202) Google Scholar), we asked whether the loss of stromal RANKL had an effect on macrophage differentiation in the LNs. We first focused on the SSMs because these cells reside in the same zone as the MRCs. SSMs express CD169, and the staining of LN sections for CD169 uncovered that this marker was markedly diminished in RanklΔCcl19 mice (Figure 2A). Given that CD169 expression in wild-type mice is lower in the medullary area, we also stained for specific ICAM-3-grabbing nonintegrin-related 1 (SIGN-R1), expressed by the MSMs but not by the SSMs (Moseman et al., 2012Moseman E.A. Iannacone M. Bosurgi L. Tonti E. Chevrier N. Tumanov A. Fu Y.X. Hacohen N. von Andrian U.H. B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity.Immunity. 2012; 36: 415-426Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). There was a clear reduction in the extent of SIGN-R1 and CD11b staining, but the formation and the position of B220+ B cell follicles appeared normal (Figure 2A). To quantify a decline in these two macrophage subsets and to assess other myeloid cell populations, we performed analyses by flow cytometry. Among live CD11b+CD11c+ cells, SSMs and MSMs were MHC-II+CD11clow and could be distinguished as CD169+F4/80− and CD169+F4/80+ cells, respectively (Figure 2B). We found that the numbers of SSMs and MSMs were significantly reduced in the mutant mice (Figure 2B). In contrast, the F4/80 single-positive macrophages were slightly increased, and the remaining double-negative macrophages that likely comprise the T cell zone macrophages (Baratin et al., 2017Baratin M. Simon L. Jorquera A. Ghigo C. Dembele D. Nowak J. Gentek R. Wienert S. Klauschen F. Malissen B. et al.T cell zone resident macrophages silently dispose of apoptotic cells in the lymph node.Immunity. 2017; 47: 349-362.e5Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar) were not affected (Figure 2C). We found no alteration in the numbers of the tissue-derived CD11c+CD11b+MHC-IIhi DCs or the LN-resident CD11c+CD11b+MHC-II+ DCs (Figure 2D). Thus, stromal RANKL is specifically required for the differentiation of the subcapsular and the medullary SM subsets. SMs relay lymph-borne antigen to B cells (Phan et al., 2007Phan T.G. Grigorova I. Okada T. Cyster J.G. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells.Nat. Immunol. 2007; 8: 992-1000Crossref PubMed Scopus (482) Google Scholar) and stimulate the immune response to viral pathogens (Chatziandreou et al., 2017Chatziandreou N. Farsakoglu Y. Palomino-Segura M. D’Antuono R. Pizzagalli D.U. Sallusto F. Lukacs-Kornek V. Uguccioni M. Corti D. Turley S.J. et al.Macrophage death following influenza vaccination initiates the inflammatory response that promotes dendritic cell function in the draining lymph node.Cell Rep. 2017; 18: 2427-2440Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, Gaya et al., 2015Gaya M. Castello A. Montaner B. Rogers N. Reis e Sousa C. Bruckbauer A. Batista F.D. Host response. Inflammation-induced disruption of SCS macrophages impairs B cell responses to secondary infection.Science. 2015; 347: 667-672Crossref PubMed Scopus (95) Google Scholar, Sagoo et al., 2016Sagoo P. Garcia Z. Breart B. Lemaître F. Michonneau D. Albert M.L. Levy Y. Bousso P. In vivo imaging of inflammasome activation reveals a subcapsular macrophage burst response that mobilizes innate and adaptive immunity.Nat. Med. 2016; 22: 64-71Crossref PubMed Scopus (83) Google Scholar). Therefore, to ascertain that their diminished number in RanklΔCcl19 mice has functional implications, we first tested the relay of immune complexes to B cells. To this end, we passively immunized RanklΔCcl19 or Ranklfl/fl mice with anti-phycoerythrin (PE) antibodies and then administered PE into the hind footpad (Phan et al., 2007Phan T.G. Grigorova I. Okada T. Cyster J.G. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells.Nat. Immunol. 2007; 8: 992-1000Crossref PubMed Scopus (482) Google Scholar). Eight hours later, popliteal LNs were processed to harvest B cells. The addition of CD45.1+ lymphocytes from the Ly5.1 congenic strain to the cell suspension allowed us to distinguish between in vivo PE uptake and PE acquisition during cell preparation. B cells from CD45.2 RanklΔCcl19 or Ranklfl/fl mice were analyzed by flow cytometry. The proportion of PE+ CD45.2 B cells was significantly lower in the conditional RANKL-deficient mice (Figure 3A). Next, we tested the infection with the vesicular stomatitis virus (VSV), known to target SSMs (Iannacone et al., 2010Iannacone M. Moseman E.A. Tonti E. Bosurgi L. Junt T. Henrickson S.E. Whelan S.P. Guidotti L.G. von Andrian U.H. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus.Nature. 2010; 465: 1079-1083Crossref PubMed Scopus (251) Google Scholar, Junt et al., 2007Junt T. Moseman E.A. Iannacone M. Massberg S. Lang P.A. Boes M. Fink K. Henrickson S.E. Shayakhmetov D.M. Di Paolo N.C. et al.Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells.Nature. 2007; 450: 110-114Crossref PubMed Scopus (630) Google Scholar). RANKL-deficient and control mice received an intra footpad (i.fp.) administration of 106 plaque-forming units (PFU) of VSV, and 6 h later, the popliteal LNs were imaged for VSV replication with the anti-VSV-glycoprotein antibody Vi10 (Honke et al., 2011Honke N. Shaabani N. Cadeddu G. Sorg U.R. Zhang D.E. Trilling M. Klingel K. Sauter M. Kandolf R. Gailus N. et al.Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus.Nat. Immunol. 2011; 13: 51-57Crossref PubMed Scopus (170) Google Scholar). Although VSV infection of CD169+ SSMs was clearly detected in the control mice, there was a significant drop in infection of RanklΔCcl19 mice (Figure 3B). Both SM subsets have been implicated in the immune response against modified vaccinia ankara (MVA) virus (Chatziandreou et al., 2017Chatziandreou N. Farsakoglu Y. Palomino-Segura M. D’Antuono R. Pizzagalli D.U. Sallusto F. Lukacs-Kornek V. Uguccioni M. Corti D. Turley S.J. et al.Macrophage death following influenza vaccination initiates the inflammatory response that promotes dendritic cell function in the draining lymph node.Cell Rep. 2017; 18: 2427-2440Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, Gaya et al., 2015Gaya M. Castello A. Montaner B. Rogers N. Reis e Sousa C. Bruckbauer A. Batista F.D. Host response. Inflammation-induced disruption of SCS macrophages impairs B cell responses to secondary infection.Science. 2015; 347: 667-672Crossref PubMed Scopus (95) Google Scholar, Sagoo et al., 2016Sagoo P. Garcia Z. Breart B. Lemaître F. Michonneau D. Albert M.L. Levy Y. Bousso P. In vivo imaging of inflammasome activation reveals a subcapsular macrophage burst response that mobilizes innate and adaptive immunity.Nat. Med. 2016; 22: 64-71Crossref PubMed Scopus (83) Google Scholar). Therefore, the mice received an i.fp. administration of 104 PFU of MVA virus, and 7 days later, the formation of germinal center B cells and plasma cells was assessed by flow cytometry. In spite of an increase in general cellularity, indicative of an ongoing immune response (Figure 3C), the capacity of the mutant mice to generate GL-7+Fas+ germinal center and CD138+ plasma B cells was abolished (Figure 3D). Altogether, these results demonstrate that stromal RANKL is a critical component for the response to viral infection by providing the signal required for SM differentiation. To address the mechanism underlying RANKL-mediated SM differentiation, we reasoned that the cell differentiation program could be directly instructed by RANKL and sought to genetically delete Rank from SMs. Both SM subsets transcribe Rank, albeit less then LECs (Figure S2A). However, a gene-targeting strategy in the myeloid lineage via Cd11c (Itgαx)-cre or LysM (Lyz2)-cre mice crossed with Rankfl/fl mice (Rios et al., 2016Rios D. Wood M.B. Li J. Chassaing B. Gewirtz A.T. Williams I.R. Antigen sampling by intestinal M cells is the principal pathway initiating mucosal IgA production to commensal enteric bacteria.Mucosal Immunol. 2016; 9: 907-916Crossref PubMed Scopus (141) Google Scholar) had no effect on the SMs (F" @default.
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• W2949761254 title "Lymph Node Mesenchymal and Endothelial Stromal Cells Cooperate via the RANK-RANKL Cytokine Axis to Shape the Sinusoidal Macrophage Niche" @default.
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