The Stromal Niche Guarding the Gatekeepers
2019; Cell Press; Volume: 50; Issue: 6 Linguagem: Inglês
10.1016/j.immuni.2019.05.019
ISSN1097-4180
AutoresSpyridon Makris, Sophie E. Acton,
Tópico(s)Lymphatic System and Diseases
ResumoIn this issue of Immunity, Mondor et al., 2019Mondor I. Baratin M. Lagueyrie M. Saro L. Henri S. Gentek R. Suerinck D. Kastenmüller W. Jiang J.X. Bajénoff M. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche.Immunity. 2019; 50 (this issue): 1453-1466Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and Camara et al., 2019Camara A. Corderio O.G. Alloush F. Sponsel J. Chypre M. Onder L. Asano K. Tanaka M. Yagita H. Ludewig B. et al.Lymph node mesenchymal and endothelial stromal cells cooperate via RANK-RANKL to shape the sinusoidal macrophage niche.Immunity. 2019; 50 (this issue): 1467-1481Scopus (47) Google Scholar show that lymphatic endothelial cells are essential components of the niche that forms and maintains the subcapsular sinusoidal macrophage network in homeostasis and throughout an immune challenge. In this issue of Immunity, Mondor et al., 2019Mondor I. Baratin M. Lagueyrie M. Saro L. Henri S. Gentek R. Suerinck D. Kastenmüller W. Jiang J.X. Bajénoff M. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche.Immunity. 2019; 50 (this issue): 1453-1466Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and Camara et al., 2019Camara A. Corderio O.G. Alloush F. Sponsel J. Chypre M. Onder L. Asano K. Tanaka M. Yagita H. Ludewig B. et al.Lymph node mesenchymal and endothelial stromal cells cooperate via RANK-RANKL to shape the sinusoidal macrophage niche.Immunity. 2019; 50 (this issue): 1467-1481Scopus (47) Google Scholar show that lymphatic endothelial cells are essential components of the niche that forms and maintains the subcapsular sinusoidal macrophage network in homeostasis and throughout an immune challenge. Macrophages are strategically positioned within tissues and have numerous roles in tissue development and homeostasis and during inflammation and its resolution. The recent identification of transcription factors central to the identity of tissue-resident macrophages has been coupled with genetic models enabling the tracing of macrophage origins and development. It is clear that signals from the surrounding tissue drive and maintain the transcriptional programs that determine the phenotype and function of resident macrophages (Glass and Natoli, 2016Glass C.K. Natoli G. Molecular control of activation and priming in macrophages.Nat. Immunol. 2016; 17: 26-33Crossref PubMed Scopus (311) Google Scholar). In this issue of Immunity, Mondor et al., 2019Mondor I. Baratin M. Lagueyrie M. Saro L. Henri S. Gentek R. Suerinck D. Kastenmüller W. Jiang J.X. Bajénoff M. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche.Immunity. 2019; 50 (this issue): 1453-1466Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and Camara et al., 2019Camara A. Corderio O.G. Alloush F. Sponsel J. Chypre M. Onder L. Asano K. Tanaka M. Yagita H. Ludewig B. et al.Lymph node mesenchymal and endothelial stromal cells cooperate via RANK-RANKL to shape the sinusoidal macrophage niche.Immunity. 2019; 50 (this issue): 1467-1481Scopus (47) Google Scholar report that a subset of lymph-node-resident macrophages, the subcapsular sinus macrophages (SSMs), differentiate and are replenished within a subcapsular sinus niche and provide insight into this niche environment. These findings add a new perspective to cellular plasticity of macrophages and stromal cells within the lymph node microenvironment. The origin of resident macrophages varies tissue by tissue, and their specific phenotype is driven by the niche signals they encounter (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 (85) Google Scholar). Yolk sac progenitors colonize the fetal liver and give rise to macrophage precursors, which colonize all embryonic tissues in a CX3CR1-dependent manner. Brain-, lung-, and liver-resident macrophages of embryonic origin are self-maintained throughout life. However, in the liver, when Kuppfer cell numbers are diminished during infection they are temporarily replaced by recruited monocytes that differentiate and occupy the niche. Evidence suggests that upon resolution, the newly recruited cells have a competitive disadvantage such that the original embryonic macrophage population retains its prominence over time (van de Laar et al., 2016van de Laar L. Saelens W. De Prijck S. Martens L. Scott C.L. Van Isterdael G. Hoffmann E. Beyaert R. Saeys Y. Lambrecht B.N. Guilliams M. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages.Immunity. 2016; 44: 755-768Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar). In contrast, embryonic-derived resident macrophages of the heart, dermis, and pancreas are replaced by bone marrow (BM)-derived macrophages (Bain et al., 2013Bain C.C. Scott C.L. Uronen-Hansson H. Gudjonsson S. Jansson O. Grip O. Guilliams M. Malissen B. Agace W.W. Mowat A.M. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors.Mucosal Immunol. 2013; 6: 498-510Crossref PubMed Scopus (588) Google Scholar). It is not yet clear how these studies in mice translate to healthy aging in humans, but evidence suggests there might also be an increased contribution of BM-derived macrophages in humans after infection and with increasing age (Perdiguero and Geissmann, 2016Perdiguero E.G. Geissmann F. The development and maintenance of resident macrophages.Nat. Immunol. 2016; 17: 2-8Crossref PubMed Scopus (372) Google Scholar). Lymph nodes are meeting places for immune cells and are strategically positioned throughout the body to orchestrate adaptive immune responses. Lymph node development occurs late in gestation through budding of the lymph sac. Final colonization of lymph node structures by resident macrophages is completed after birth (Detmar and Hirakawa, 2002Detmar M. Hirakawa S. The formation of lymphatic vessels and its importance in the setting of malignancy.J. Exp. Med. 2002; 196: 713-718Crossref PubMed Scopus (64) Google Scholar). Lymph nodes house five different populations of resident macrophages, each strategically positioned, and their phenotype is defined by their anatomical microenvironment. T cell zone macrophages within the paracortex are professional scavengers that remove apoptotic cells. Tingible body macrophages carry out the equivalent function in germinal centers. Medullary cord macrophages reside within the lymph node parenchyma and the medullary cord (Bellomo et al., 2018Bellomo A. Gentek R. Bajénoff M. Baratin M. Lymph node macrophages: scavengers, immune sentinels and trophic effectors.Cell. Immunol. 2018; 330: 168-174Crossref PubMed Scopus (33) Google Scholar), and medullary sinus macrophages (MSMs) and SSMs line the entry and exit points of lymphatic flow, where they are positioned to sample pathogens in draining lymph. SSMs can rapidly respond to pathogens or inflammatory stimuli by secreting inflammatory cytokines to induce infiltration of neutrophils, NK cells, and monocytes and migrate into follicles to present antigen to B cells or prime follicular dendritic cells. Furthermore, SSMs act as “plugs” to block the activation of B lymphocytes to secondary infections (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 (94) Google Scholar). In their study, Mondor et al., 2019Mondor I. Baratin M. Lagueyrie M. Saro L. Henri S. Gentek R. Suerinck D. Kastenmüller W. Jiang J.X. Bajénoff M. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche.Immunity. 2019; 50 (this issue): 1453-1466Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar examined the developmental origin of SSMs and their maintenance in response to immune challenge. In combination with Cx3cr1-GFP labeling, pulse labeling hemogenically active endothelial cells of the yolk sac in Cdh5CreERT2 mice at embryonic day 7.5 (E7.5) elegantly showed that at E19, approximately 24% of SSMs were derived from the yolk sac. Postnatally, yolk-sac-derived SSMs are diluted and gradually replaced by BM-derived monocytes to establish the adult SSM population. The authors used shielded bone marrow chimeras to determine that migration of CCR2+ monocytes was necessary for establishing the adult SSM network. Furthermore, recruited monocytes proliferated locally within the lymph node given that multicolored bone marrow transferred from Rag2−/−UbiquitinCreERT2Ubow into neonates developed monocultured foci of SSMs. At the steady state, the authors used iCxc3r1Ubow mice to show that SSMs clonally self-maintain in situ. Mondor et al., 2019Mondor I. Baratin M. Lagueyrie M. Saro L. Henri S. Gentek R. Suerinck D. Kastenmüller W. Jiang J.X. Bajénoff M. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche.Immunity. 2019; 50 (this issue): 1453-1466Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar perturbed the SSM network by subcutaneous injection of clodronate liposome or by bacterial or viral infection. In all cases, they found that BM-derived monocytes were required for replenishing the SSM network and were recruited to draining lymph nodes within 4–7 days. Together with the proliferation of residual SSMs, this wave of monocytes fully restored the SSM network. Macrophages require factors such as CX3CL1, IL-34, and CSF-1 for development, differentiation, and survival. However, because lymph nodes house multiple resident macrophage populations with different functions and phenotypes, we must examine the local microenvironment to understand their individual niches. Mondor et al., 2019Mondor I. Baratin M. Lagueyrie M. Saro L. Henri S. Gentek R. Suerinck D. Kastenmüller W. Jiang J.X. Bajénoff M. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche.Immunity. 2019; 50 (this issue): 1453-1466Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar investigated the local source of CSF-1 and found a strong association with the endothelial receptor LYVE-1 in both the capsule and the medulla. Using an inducible Prox1ΔCSF mouse model to delete CSF-1 from lymphatic endothelial cells (LECs), they confirmed that LECs produced CSF-1 (Figure 1). Deletion of CSF-1 from LECs caused a drastic decrease in SSMs in the capsule and MSMs in the medulla but did not affect other resident populations in the paracortex or resident macrophage populations in non-lymphoid tissues. Furthermore, LEC-derived CSF-1 was required for engraftment of transferred wild-type (WT) monocytes, suggesting that CSF-1 is critical for both SSM homeostasis and replenishment. Revealing that LECs in the sinus produce CSF-1 is the first step to understanding the control of resident macrophages. We can now ask how, why, and when LECs are instructed to secrete CSF-1 and other factors. Camara et al., 2019Camara A. Corderio O.G. Alloush F. Sponsel J. Chypre M. Onder L. Asano K. Tanaka M. Yagita H. Ludewig B. et al.Lymph node mesenchymal and endothelial stromal cells cooperate via RANK-RANKL to shape the sinusoidal macrophage niche.Immunity. 2019; 50 (this issue): 1467-1481Scopus (47) Google Scholar identified the importance of lymph node stromal cells in shaping the SSM niche in developing lymph nodes. Reactive activator of NF-κB ligand (RANKL), produced by mesenchymal lymphoid tissue organizer cells, is critical, and RANKL-deficient mice fail to develop lymph nodes. In adult mice, RANKL is specifically produced by marginal reticular cells (MRCs). However, the authors showed that specific deletion of RANKL on CCL19+ MRCs had little effect on lymph node development and architecture. On closer inspection, these lymph nodes had diminished SSM and MSM populations in the subcapsular sinus and the medulla. Consequently, B cell activation and germinal center formation were impaired in response to modified vaccinia ankara. To determine whether RANKL directly stimulates SSMs, Camara et al., 2019Camara A. Corderio O.G. Alloush F. Sponsel J. Chypre M. Onder L. Asano K. Tanaka M. Yagita H. Ludewig B. et al.Lymph node mesenchymal and endothelial stromal cells cooperate via RANK-RANKL to shape the sinusoidal macrophage niche.Immunity. 2019; 50 (this issue): 1467-1481Scopus (47) Google Scholar depleted RANK from CD169+ cells by using Cd169-cre. These mice exhibited a diminished SSM network, but medullary macrophages were unaffected. However, in the absence of RANK, the subcapsular sinus was not devoid of macrophages but rather was populated with SIGN-R1+ cells, which limited the recruitment and expansion of transferred WT RANK+ BM-derived monocytes. Camara et al., 2019Camara A. Corderio O.G. Alloush F. Sponsel J. Chypre M. Onder L. Asano K. Tanaka M. Yagita H. Ludewig B. et al.Lymph node mesenchymal and endothelial stromal cells cooperate via RANK-RANKL to shape the sinusoidal macrophage niche.Immunity. 2019; 50 (this issue): 1467-1481Scopus (47) Google Scholar found that this mechanism was specific to the SSMs of the lymph node and that CD169-driven depletion of RANK did not affect resident macrophages in other tissues. Deletion of RANKL from CCL19+ MRCs resulted in a more significant disruption of the SSMs than the deletion of RANK from the CD169+ macrophages. Camara et al., 2019Camara A. Corderio O.G. Alloush F. Sponsel J. Chypre M. Onder L. Asano K. Tanaka M. Yagita H. Ludewig B. et al.Lymph node mesenchymal and endothelial stromal cells cooperate via RANK-RANKL to shape the sinusoidal macrophage niche.Immunity. 2019; 50 (this issue): 1467-1481Scopus (47) Google Scholar therefore asked whether RANKL exerted its effect through additional mechanisms. Indeed, LECs also respond directly to RANKL stimulation, and deletion of RANK from LECs in an inducible Prox1-cre mouse also caused a reduction in SSMs. Interestingly, this reduction in SSMs was only observed when RANK was depleted at or shortly after birth. The authors further showed that RANK activation of LECs was important for reconstitution of the sinus macrophage networks in adult mice. SSM replenishment was delayed for a prolonged period following CpG-induced depletion when RANK was depleted in LECs. In parallel with findings from Mondor et al., 2019Mondor I. Baratin M. Lagueyrie M. Saro L. Henri S. Gentek R. Suerinck D. Kastenmüller W. Jiang J.X. Bajénoff M. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche.Immunity. 2019; 50 (this issue): 1453-1466Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, Camara et al., 2019Camara A. Corderio O.G. Alloush F. Sponsel J. Chypre M. Onder L. Asano K. Tanaka M. Yagita H. Ludewig B. et al.Lymph node mesenchymal and endothelial stromal cells cooperate via RANK-RANKL to shape the sinusoidal macrophage niche.Immunity. 2019; 50 (this issue): 1467-1481Scopus (47) Google Scholar showed that the LECs in the subcapsular sinus needed to reactivate the niche in order to reconstitute the SSM network, and to do this, LECs required activation via RANK. These findings demonstrate that RANK-activated LECs are central for the formation of the SSM niche and also the re-establishment of SSM networks after immune activation. We can now probe the roles that RANK-activated LECs might play in the postnatal dilution of embryonic macrophages as described by Mondor et al., 2019Mondor I. Baratin M. Lagueyrie M. Saro L. Henri S. Gentek R. Suerinck D. Kastenmüller W. Jiang J.X. Bajénoff M. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche.Immunity. 2019; 50 (this issue): 1453-1466Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar. RANK affects an array of transcriptional changes in LECs, including CSF-1, which Mondor et al. have shown is vital for the SSM niche. RANK is also required for expression of mucosal vascular addressin cell-adhesion molecule 1 (MAdCAM-1) on LECs (Figure 1). Given that MRCs, LECs, and macrophages can all respond directly to inflammatory signals and show remarkable plasticity of phenotype, the niche for SSMs can rapidly adapt as required during the course of immune reactions and their resolution. In summary, Mondor et al., 2019Mondor I. Baratin M. Lagueyrie M. Saro L. Henri S. Gentek R. Suerinck D. Kastenmüller W. Jiang J.X. Bajénoff M. Lymphatic endothelial cells are essential components of the subcapsular sinus macrophage niche.Immunity. 2019; 50 (this issue): 1453-1466Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar and Camara et al., 2019Camara A. Corderio O.G. Alloush F. Sponsel J. Chypre M. Onder L. Asano K. Tanaka M. Yagita H. Ludewig B. et al.Lymph node mesenchymal and endothelial stromal cells cooperate via RANK-RANKL to shape the sinusoidal macrophage niche.Immunity. 2019; 50 (this issue): 1467-1481Scopus (47) Google Scholar have identified a central role of LECs in the environmental niche for SSM homing, differentiation, and maintenance through both development and adulthood. LECs provide CSF-1 to maintain the SSM niche. RANKL, produced by MRCs, has a dual role: it is essential for the priming of LECs and for the homing of monocytes to replace lost SSMs after inflammation. These findings provide exciting avenues for studying the crosstalk between immune cells and stromal cells in driving plasticity and remind us that to fully understand immune function, we must consider the spatial organization and cellular complexity within the tissue microenvironment. Lymphatic Endothelial Cells Are Essential Components of the Subcapsular Sinus Macrophage NicheMondor et al.ImmunityApril 30, 2019In BriefMondor et al. demonstrate that subcapsular sinus macrophages (SSMs) self-maintain by proliferation in the adult mouse lymph node and that homeostasis of SSMs and medullary sinus macrophages (MSMs) relies on secretion of CSF-1 by neighboring lymphatic endothelial cells (LECs). Full-Text PDF Open ArchiveLymph Node Mesenchymal and Endothelial Stromal Cells Cooperate via the RANK-RANKL Cytokine Axis to Shape the Sinusoidal Macrophage NicheCamara et al.ImmunityJune 11, 2019In BriefTissue-resident macrophages acquire defining genetic programs in response to signals from surrounding cells. Camara et al. reveal that mesenchymal cells and lymphatic endothelial cells within the lymph node interact via RANK-RANKL to generate a niche environment that supports the differentiation of sinusoidal macrophages and their maintenance after an inflammatory challenge. Full-Text PDF Open Archive
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