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• W1977202406 abstract "Macrophages frequently infiltrate tumors and can enhance cancer growth, yet the origins of the macrophage response are not well understood. Here we address molecular mechanisms of macrophage production in a conditional mouse model of lung adenocarcinoma. We report that overproduction of the peptide hormone Angiotensin II (AngII) in tumor-bearing mice amplifies self-renewing hematopoietic stem cells (HSCs) and macrophage progenitors. The process occurred in the spleen but not the bone marrow, and was independent of hemodynamic changes. The effects of AngII required direct hormone ligation on HSCs, depended on S1P1 signaling, and allowed the extramedullary tissue to supply new tumor-associated macrophages throughout cancer progression. Conversely, blocking AngII production prevented cancer-induced HSC and macrophage progenitor amplification and thus restrained the macrophage response at its source. These findings indicate that AngII acts upstream of a potent macrophage amplification program and that tumors can remotely exploit the hormone’s pathway to stimulate cancer-promoting immunity. Macrophages frequently infiltrate tumors and can enhance cancer growth, yet the origins of the macrophage response are not well understood. Here we address molecular mechanisms of macrophage production in a conditional mouse model of lung adenocarcinoma. We report that overproduction of the peptide hormone Angiotensin II (AngII) in tumor-bearing mice amplifies self-renewing hematopoietic stem cells (HSCs) and macrophage progenitors. The process occurred in the spleen but not the bone marrow, and was independent of hemodynamic changes. The effects of AngII required direct hormone ligation on HSCs, depended on S1P1 signaling, and allowed the extramedullary tissue to supply new tumor-associated macrophages throughout cancer progression. Conversely, blocking AngII production prevented cancer-induced HSC and macrophage progenitor amplification and thus restrained the macrophage response at its source. These findings indicate that AngII acts upstream of a potent macrophage amplification program and that tumors can remotely exploit the hormone’s pathway to stimulate cancer-promoting immunity. ▸ AngII-AGTR1A signaling promotes splenic amplification of macrophage progenitors ▸ AngII retains HSCs and macrophage progenitors in spleen by repressing S1P1 sensing ▸ Mouse NSCLC exploits the AngII pathway to amplify the macrophage response ▸ Controlling AngII production restrains tumor-promoting macrophage response in mice Macrophages are tissue-resident white blood cells that protect against infection and injury. Some macrophages, however, inversely affect prognosis by contributing to cancer. Macrophages that infiltrate the tumor stroma are often referred to as tumor-associated macrophages (TAMs). Experimental models using mice have shown that TAMs can facilitate tumor progression by promoting inflammation, stimulating angiogenesis, enhancing tumor cell migration and metastasis, and suppressing antitumor immunity (De Palma et al., 2007De Palma M. Murdoch C. Venneri M.A. Naldini L. Lewis C.E. Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications.Trends Immunol. 2007; 28: 519-524Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar; Mantovani et al., 2008Mantovani A. Allavena P. Sica A. Balkwill F. Cancer-related inflammation.Nature. 2008; 454: 436-444Crossref PubMed Scopus (7906) Google Scholar; Grivennikov et al., 2010Grivennikov S.I. Greten F.R. Karin M. Immunity, inflammation, and cancer.Cell. 2010; 140: 883-899Abstract Full Text Full Text PDF PubMed Scopus (7472) Google Scholar; Qian and Pollard, 2010Qian B.Z. Pollard J.W. Macrophage diversity enhances tumor progression and metastasis.Cell. 2010; 141: 39-51Abstract Full Text Full Text PDF PubMed Scopus (3420) Google Scholar; Hanahan and Coussens, 2012Hanahan D. Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment.Cancer Cell. 2012; 21: 309-322Abstract Full Text Full Text PDF PubMed Scopus (2915) Google Scholar). Clinical studies have further reported that the presence of TAMs correlates with adverse outcome and shorter survival in various cancer types, including non-small-cell lung cancer (NSCLC) (Zhang et al., 2011aZhang B. Yao G. Zhang Y. Gao J. Yang B. Rao Z. Gao J. M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma.Clinics (Sao Paulo). 2011; 66: 1879-1886Crossref PubMed Scopus (132) Google Scholar; Zhang et al., 2011bZhang B.C. Gao J. Wang J. Rao Z.G. Wang B.C. Gao J.F. Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma.Med. Oncol. 2011; 28: 1447-1452Crossref PubMed Scopus (99) Google Scholar), breast cancer (DeNardo et al., 2011DeNardo D.G. Brennan D.J. Rexhepaj E. Ruffell B. Shiao S.L. Madden S.F. Gallagher W.M. Wadhwani N. Keil S.D. Junaid S.A. et al.Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.Cancer Discov. 2011; 1: 54-67Crossref PubMed Scopus (529) Google Scholar), and Hodgkin’s lymphoma (Steidl et al., 2010Steidl C. Lee T. Shah S.P. Farinha P. Han G. Nayar T. Delaney A. Jones S.J. Iqbal J. Weisenburger D.D. et al.Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma.N. Engl. J. Med. 2010; 362: 875-885Crossref PubMed Scopus (999) Google Scholar). TAMs are often the most abundant host cell population within the tumor stroma, but because they are short-lived and do not proliferate in situ, TAMs must be continuously replaced throughout cancer progression (Sawanobori et al., 2008Sawanobori Y. Ueha S. Kurachi M. Shimaoka T. Talmadge J.E. Abe J. Shono Y. Kitabatake M. Kakimi K. Mukaida N. Matsushima K. Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice.Blood. 2008; 111: 5457-5466Crossref PubMed Scopus (298) Google Scholar; Movahedi et al., 2010Movahedi K. Laoui D. Gysemans C. Baeten M. Stangé G. Van den Bossche J. Mack M. Pipeleers D. In’t Veld P. De Baetselier P. Van Ginderachter J.A. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes.Cancer Res. 2010; 70: 5728-5739Crossref PubMed Scopus (843) Google Scholar; Cortez-Retamozo et al., 2012Cortez-Retamozo V. Etzrodt M. Newton A. Rauch P.J. Chudnovskiy A. Berger C. Ryan R.J. Iwamoto Y. Marinelli B. Gorbatov R. et al.Origins of tumor-associated macrophages and neutrophils.Proc. Natl. Acad. Sci. USA. 2012; 109: 2491-2496Crossref PubMed Scopus (456) Google Scholar). Inflammatory tissue macrophages descend from circulating monocytes, which are initially produced in bone marrow by hematopoietic stem cells (HSCs) (van Furth and Cohn, 1968van Furth R. Cohn Z.A. The origin and kinetics of mononuclear phagocytes.J. Exp. Med. 1968; 128: 415-435Crossref PubMed Scopus (972) Google Scholar; Geissmann et al., 2010Geissmann F. Manz M.G. Jung S. Sieweke M.H. Merad M. Ley K. Development of monocytes, macrophages, and dendritic cells.Science. 2010; 327: 656-661Crossref PubMed Scopus (2180) Google Scholar). These macrophages are distinct from Myb-independent macrophages that develop in the embryo before the appearance of HSCs (Schulz et al., 2012Schulz C. Gomez Perdiguero E. Chorro L. Szabo-Rogers H. Cagnard N. Kierdorf K. Prinz M. Wu B. Jacobsen S.E. Pollard J.W. et al.A lineage of myeloid cells independent of Myb and hematopoietic stem cells.Science. 2012; 336: 86-90Crossref PubMed Scopus (1737) Google Scholar). Monocyte production by HSCs involves the generation of discrete cell progenitor intermediates, including macrophage and dendritic cell progenitors (MDPs) (Fogg et al., 2006Fogg D.K. Sibon C. Miled C. Jung S. Aucouturier P. Littman D.R. Cumano A. Geissmann F. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells.Science. 2006; 311: 83-87Crossref PubMed Scopus (774) Google Scholar). These hematopoietic stem and progenitor cells (HSPCs) can divide, whereas monocytes and macrophages typically do not (van Furth and Cohn, 1968van Furth R. Cohn Z.A. The origin and kinetics of mononuclear phagocytes.J. Exp. Med. 1968; 128: 415-435Crossref PubMed Scopus (972) Google Scholar). Thus, the prevailing model of macrophage response implies that fundamental amplification and differentiation occur in the bone marrow. Despite the prevalence of this linear model of macrophage production, HSPCs constitutively exit the bone marrow (Goodman and Hodgson, 1962Goodman J.W. Hodgson G.S. Evidence for stem cells in the peripheral blood of mice.Blood. 1962; 19: 702-714PubMed Google Scholar; Wright et al., 2001Wright D.E. Wagers A.J. Gulati A.P. Johnson F.L. Weissman I.L. Physiological migration of hematopoietic stem and progenitor cells.Science. 2001; 294: 1933-1936Crossref PubMed Scopus (773) Google Scholar) and, during inflammation, support myelopoiesis in extramedullary tissue (Massberg et al., 2007Massberg S. Schaerli P. Knezevic-Maramica I. Köllnberger M. Tubo N. Moseman E.A. Huff I.V. Junt T. Wagers A.J. Mazo I.B. von Andrian U.H. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues.Cell. 2007; 131: 994-1008Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar). The spleen’s red pulp can be a site of HSPC activity during disease in both humans and mice (Freedman and Saunders, 1981Freedman M.H. Saunders E.F. Hematopoiesis in the human spleen.Am. J. Hematol. 1981; 11: 271-275Crossref PubMed Scopus (29) Google Scholar; Cortez-Retamozo et al., 2012Cortez-Retamozo V. Etzrodt M. Newton A. Rauch P.J. Chudnovskiy A. Berger C. Ryan R.J. Iwamoto Y. Marinelli B. Gorbatov R. et al.Origins of tumor-associated macrophages and neutrophils.Proc. Natl. Acad. Sci. USA. 2012; 109: 2491-2496Crossref PubMed Scopus (456) Google Scholar; Dutta et al., 2012Dutta P. Courties G. Wei Y. Leuschner F. Gorbatov R. Robbins C.S. Iwamoto Y. Thompson B. Carlson A.L. Heidt T. et al.Myocardial infarction accelerates atherosclerosis.Nature. 2012; 487: 325-329Crossref PubMed Scopus (753) Google Scholar). The newly produced cells supplement a reservoir of splenic monocytes (Swirski et al., 2009Swirski F.K. Nahrendorf M. Etzrodt M. Wildgruber M. Cortez-Retamozo V. Panizzi P. Figueiredo J.L. Kohler R.H. Chudnovskiy A. Waterman P. et al.Identification of splenic reservoir monocytes and their deployment to inflammatory sites.Science. 2009; 325: 612-616Crossref PubMed Scopus (1573) Google Scholar), which are readily mobilized to contribute large numbers of macrophages to distant lesions. This process occurs after myocardial infarction (Leuschner et al., 2012Leuschner F. Rauch P.J. Ueno T. Gorbatov R. Marinelli B. Lee W.W. Dutta P. Wei Y. Robbins C. Iwamoto Y. et al.Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis.J. Exp. Med. 2012; 209: 123-137Crossref PubMed Scopus (362) Google Scholar) and during the progression of atherosclerosis (Robbins et al., 2012Robbins C.S. Chudnovskiy A. Rauch P.J. Figueiredo J.L. Iwamoto Y. Gorbatov R. Etzrodt M. Weber G.F. Ueno T. van Rooijen N. et al.Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions.Circulation. 2012; 125: 364-374Crossref PubMed Scopus (338) Google Scholar) and cancer (Cortez-Retamozo et al., 2012Cortez-Retamozo V. Etzrodt M. Newton A. Rauch P.J. Chudnovskiy A. Berger C. Ryan R.J. Iwamoto Y. Marinelli B. Gorbatov R. et al.Origins of tumor-associated macrophages and neutrophils.Proc. Natl. Acad. Sci. USA. 2012; 109: 2491-2496Crossref PubMed Scopus (456) Google Scholar). Although the bone marrow maintains the monocyte repertoire in steady state, the monocyte production can be outsourced during inflammatory diseases. Cancer-induced extramedullary monocytopoiesis promotes generation of cells with heightened tumor-promoting functions (Cortez-Retamozo et al., 2012Cortez-Retamozo V. Etzrodt M. Newton A. Rauch P.J. Chudnovskiy A. Berger C. Ryan R.J. Iwamoto Y. Marinelli B. Gorbatov R. et al.Origins of tumor-associated macrophages and neutrophils.Proc. Natl. Acad. Sci. USA. 2012; 109: 2491-2496Crossref PubMed Scopus (456) Google Scholar; Ugel et al., 2012Ugel S. Peranzoni E. Desantis G. Chioda M. Walter S. Weinschenk T. Ochando J.C. Cabrelle A. Mandruzzato S. Bronte V. Immune Tolerance to Tumor Antigens Occurs in a Specialized Environment of the Spleen.Cell Rep. 2012; 2: 628-639Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar); however, the molecular mechanisms that drive such response remain largely unknown. We investigated the macrophage response by using a conditional genetic mouse model of lung adenocarcinoma (hereafter referred to as KP). This model produces autochtonous tumors from a few somatic cells via Cre-recombinase activation of oncogenic Kras and inactivation of p53 (DuPage et al., 2009DuPage M. Dooley A.L. Jacks T. Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase.Nat. Protoc. 2009; 4: 1064-1072Crossref PubMed Scopus (557) Google Scholar). Tumors in KP mice present genetic alterations that are frequently found in the human disease, progress to high-grade tumors, and are chronically infiltrated by tumor-promoting macrophages. KP mice thus provide an opportunity to study the macrophage response under in vivo conditions that mirror central aspects of the human disease. Our KP mice studies showed that increased AngII augments the production of splenic HSPCs and consequently facilitates TAM supply from extramedullary tissue throughout cancer progression. We investigated AngII because it interacts with mononuclear phagocytes and promotes inflammation (AbdAlla et al., 2004AbdAlla S. Lother H. Langer A. el Faramawy Y. Quitterer U. Factor XIIIA transglutaminase crosslinks AT1 receptor dimers of monocytes at the onset of atherosclerosis.Cell. 2004; 119: 343-354Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar; Lanz et al., 2010Lanz T.V. Ding Z. Ho P.P. Luo J. Agrawal A.N. Srinagesh H. Axtell R. Zhang H. Platten M. Wyss-Coray T. Steinman L. Angiotensin II sustains brain inflammation in mice via TGF-beta.J. Clin. Invest. 2010; 120: 2782-2794Crossref PubMed Scopus (166) Google Scholar; Ma et al., 2012Ma F. Li Y. Jia L. Han Y. Cheng J. Li H. Qi Y. Du J. Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF β/Smad activation and cardiac fibrosis induced by angiotensin II.PLoS ONE. 2012; 7: e35144Crossref PubMed Scopus (202) Google Scholar), and because it is found at increased concentrations in the plasma of lung-tumor-bearing KP animals as compared to age-matched tumor-free controls (Figure 1 A). AngII is known to release monocytes from their splenic reservoir (Swirski et al., 2009Swirski F.K. Nahrendorf M. Etzrodt M. Wildgruber M. Cortez-Retamozo V. Panizzi P. Figueiredo J.L. Kohler R.H. Chudnovskiy A. Waterman P. et al.Identification of splenic reservoir monocytes and their deployment to inflammatory sites.Science. 2009; 325: 612-616Crossref PubMed Scopus (1573) Google Scholar; Shi and Pamer, 2011Shi C. Pamer E.G. Monocyte recruitment during infection and inflammation.Nat. Rev. Immunol. 2011; 11: 762-774Crossref PubMed Scopus (1841) Google Scholar) and therefore may not be involved in de novo mononuclear phagocyte production. Yet splenocytes obtained from mice infused for 1 week with AngII showed elevated colony-forming unit-macrophage (CFU-M) activity in vitro (Figures 1B and 1C). These tumor-free mice received AngII continuously via osmotic mini-pumps at a dose that replicated the plasma concentration found in tumor-bearing mice (Figure 1A). AngII-treated mice and tumor-bearing KP mice showed comparable splenic CFU-M activity (Figures 1B and 1C). These data led us to consider that AngII may drive splenic macrophage progenitor amplification. To address AngII’s role in amplifying macrophage progenitors, we quantified HSPCs ex vivo by flow cytometry in various mouse cohorts. The analyses confirmed a marked increase in total number of splenic Linlo CD117+ Sca-1+ HSCs and Linlo CD117+ Sca-1− CD115+ CD16/32+ CD34+ MDPs in AngII-treated mice as compared to control mice (9 ± 1- and 25 ± 4-fold increase for HSCs and MDPs, respectively; Figure 1D, see also Figure S1A available online). We observed similar splenic HSC and MDP responses in tumor-bearing KP mice (HSCs: 7 ± 2-fold increase in KP mice compared to control tumor-free mice; MDPs: 20 ± 6-fold increase). These responses remained detectable at week 21 after tumor initiation (Figure S1B). AngII-treated mice (Figure 1E) and KP tumor-bearing mice (data not shown) also expanded splenic common myeloid progenitors (CMPs) and granulocyte macrophage progenitors (GMPs), which are cell intermediates that derive from HSCs and produce MDPs. AngII infusion did not seem to affect other splenic lineages in this experimental setting (Figure 1D). The amplification of HSCs, CMPs, GMPs, and MDPs occurred in the spleen but not in bone marrow (Figures 1D and 1E). Finally, these cell populations were not amplified in the spleens of control mice that received osmotic mini-pumps delivering PBS only (Figure 1E). Thus, AngII alone is sufficient to trigger extramedullary macrophage progenitor amplification as found in tumor-bearing KP mice. Tumor development in KP mice did not measurably alter blood pressure (Figure S1C), suggesting that increased AngII levels in these mice did not alter hemodynamics. Nevertheless, because AngII is a known vasoconstrictor, we measured its capacity to induce hematopoietic progenitor cell expansion in the presence of the vasodilator hydralazine. Both AngII and hydralazine were continuously released by osmotic mini-pumps implanted separately in the same animals. Hydralazine treatment reduced systolic and diastolic blood pressures as expected (from 120 ± 14/91 ± 16 to 99 ± 9/65 ± 15 mmHg, mean ± SD); however, it did not alter splenic HSC/MDP amplification (Figure 1D). Thus AngII triggers a splenic HSC and macrophage progenitor response independently from its effects on hemodynamics. Based on the above results, we investigated whether the hormone acts directly on hematopoietic cells. To test this hypothesis, we first generated mouse chimeras in which expression of the AngII receptor, AGTR1A, was restricted to either hematopoietic or nonhematopoietic cells (Figure 2 A) and then measured the AngII’s capacity to amplify HSCs and MDPs in these mice. The experiments showed that the splenic response depended strictly on AngII-AGTR1A signaling in hematopoietic cells (Figure 2B). Furthermore, splenic HSCs and MDPs were amplified equally in mice with Agtr1a –/– or Agtr1a +/+ nonhematopoietic cells (Figure 2B), indicating that AngII-AGTR1A signaling in nonhematopoietic cells did not influence the hematopoietic response. In a second approach, we tracked Agtr1a +/+ and Agtr1a –/– (EGFP+) HSCs following adoptive transfer into wild-type mice that were infused with AngII. Intravital microscopy of the spleen’s red pulp (Pittet and Weissleder, 2011Pittet M.J. Weissleder R. Intravital imaging.Cell. 2011; 147: 983-991Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar) indicated that donor Agtr1a –/– HSCs failed to produce splenic colonies in vivo as compared to their Agtr1a +/+ counterparts (Figures 2C and 2D; Figure S2). This impairment was not due to an intrinsic proliferative and/or survival defect of Agtr1a –/– HSCs because both Agtr1a –/– and Agtr1a +/+ HSCs were equally able to proliferate and produce colonies in vitro (Figure 2E), and the few Agtr1a –/– HSCs that accumulated in splenic tissue produced colonies that were comparable in average size to the ones produced by Agtr1a +/+ cells (Figure 2F). Finally, we used flow cytometry to investigate the fate of transferred HSCs in recipient mice exposed to AngII. In these experiments, HSCs and recipient mice were either Agtr1a –/– or Agtr1a +/+ (Figure 2G). Donor Agtr1a –/– HSCs failed to produce monocytic cells (defined as CD11b+ Ly-6Chi [B220, CD19, CD90.2, DX5, NK1.1, Ly-6G, F4/80, CD11c]lo), whereas Agtr1a +/+ HSCs efficiently engendered a monocytic progeny even in Agtr1a –/– recipient animals. From these experiments, we concluded that: (1) HSCs sense AngII directly, (2) the HSC response does not depend on AngII-AGTR1A signaling in nonhematopoietic cells, and (3) this sensing mechanism amplifies a macrophage progenitor response in vivo. We considered that the hormone might amplify splenic HSCs and macrophage progenitors by inducing them to proliferate; however, analyses conducted both ex vivo (Figure 3 A) and in vitro (Figure S3A) excluded this possibility. Alternatively, the hormone could retain HSPCs that travel through extramedullary tissue (Wright et al., 2001Wright D.E. Wagers A.J. Gulati A.P. Johnson F.L. Weissman I.L. Physiological migration of hematopoietic stem and progenitor cells.Science. 2001; 294: 1933-1936Crossref PubMed Scopus (773) Google Scholar). To test this hypothesis, we established parabiosis between two AngII-infused mice (or two control mice) until splenic HSC equilibration (Massberg et al., 2007Massberg S. Schaerli P. Knezevic-Maramica I. Köllnberger M. Tubo N. Moseman E.A. Huff I.V. Junt T. Wagers A.J. Mazo I.B. von Andrian U.H. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues.Cell. 2007; 131: 994-1008Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar) and then measured chimerism of parabiont-derived splenic HSCs after separating the parabionts. The separation prevents further cell exchange between animals; thus, new cells that accumulate in the spleen predominantly originate from the host, and the relative amount of parabiont-derived HSCs that remain in the tissue indicates their residence time (Liu et al., 2007Liu K. Waskow C. Liu X. Yao K. Hoh J. Nussenzweig M. Origin of dendritic cells in peripheral lymphoid organs of mice.Nat. Immunol. 2007; 8: 578-583Crossref PubMed Scopus (354) Google Scholar). This experimental approach showed that exposure to AngII significantly increases the retention of HSCs in the spleen (Figure 3B). We then investigated splenic HSC retention in tumor-bearing KP mice. This involved parabiosis between two KP mice (or two control mice) and measuring chimerism by using the method detailed above. This experiment further indicated that KP cancer increases splenic HSC retention (Figure 3C). We thus concluded that both AngII and cancer alter splenic HSC trafficking in vivo. Our next goal was to define how AngII signaling favors retention of HSCs and macrophage progenitors in the spleen. We investigated signaling through sphingosine-1-phosphate receptor 1 (S1P1, also referred to as S1PR1) because this Gαi-coupled receptor is known to promote HSC recirculation (Massberg et al., 2007Massberg S. Schaerli P. Knezevic-Maramica I. Köllnberger M. Tubo N. Moseman E.A. Huff I.V. Junt T. Wagers A.J. Mazo I.B. von Andrian U.H. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues.Cell. 2007; 131: 994-1008Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar). We confirmed that HSCs and macrophage progenitors––but not monocytes––expressed S1p1 at detectable levels in steady state (Figure S3B); however, these cells strongly repressed S1p1 expression in mice exposed to AngII (Figure 3E). Furthermore, HSCs failed to downregulate S1p1 expression in Agtr1a –/– mice exposed to AngII in vivo (Figure 3D), and purified HSCs subjected to AngII in vitro downregulated S1p1 only if they expressed AGTR1A (Figure 3E). These findings indicate that AngII-mediated repression of S1p1 in HSCs requires direct signaling through the AGTR1A receptor. In accordance with the above findings, we found that splenic progenitors obtained from AngII-infused mice (i.e., cells that had downregulated S1p1 expression in vivo) lost their ability to migrate toward an S1P gradient ex vivo (Figure 3F). Control experiments showed that the same cells remained capable of migrating toward the cytokine SDF-1α and thus remained biologically active (Figure S3C). Also, in vivo administration of the small-molecule inhibitor FTY720, which impairs S1P sensing by S1P1 (Schwab and Cyster, 2007Schwab S.R. Cyster J.G. Finding a way out: lymphocyte egress from lymphoid organs.Nat. Immunol. 2007; 8: 1295-1301Crossref PubMed Scopus (487) Google Scholar), was sufficient to promote the accumulation of HSCs in the spleen (Figure 3G). We then assessed whether the splenic hematopoietic response mediated by AngII indeed depends on S1P1 signaling. To this end, we engineered both S1p1 const CD45.1 + EGFP + HSCs (i.e., HSCs that expressed S1P1 constitutively and were tracked according to CD45.1 and EGFP expression) and S1p1 norm CD45.2 + EGFP + HSCs (i.e., HSCs that could downregulate S1P1 normally and were tracked according to CD45.2 and EGFP expression). We used a competitive assay to test these two HSC populations’ capacity to produce monocytic cells in response to AngII in vivo. Specifically, equal numbers of the two HSC populations were coinjected into EGFP− recipient mice, which were infused with AngII. The monocyte progeny of donor EGFP+ HSCs were analyzed 7 days later by flow cytometry (Figure 3H). S1p1 norm HSC-derived monocytes outnumbered their S1p1 const counterparts by ∼4:1, indicating that AngII-mediated S1p1 downregulation in HSCs directly amplifies monocytes in vivo (Figures 3I and 3J). Splenic HSCs decreased S1p1 expression in tumor-bearing KP mice as expected (Figure 3K); however, administering either the AGTR1A antagonist losartan or the Angiotensin converting enzyme inhibitor enalapril (used to decrease AngII levels) prevented this process (Figure 3K). Based on these findings, we investigated whether reducing AngII production in KP mice by injecting enalapril could prevent cancer-induced HSC and macrophage progenitor amplification and thus restrain the TAM response. Initially, we analyzed KP mice at 12 weeks after tumor initiation and 5 days after reducing AngII production with enalapril (Figure 4 A). In this experimental setting, temporarily interrupting AngII production did not detectably affect tumor burden (data not shown) but did restrain the amplification of splenic HSCs and HSC-derived MDPs, monocytes, and lung macrophages (Figure 4B). Lung macrophages were defined as F4/80+ [B220, CD19, CD90.2, DX5, NK1.1, Ly-6G]−/lo. These cells express CD11b at varying levels (Cortez-Retamozo et al., 2012Cortez-Retamozo V. Etzrodt M. Newton A. Rauch P.J. Chudnovskiy A. Berger C. Ryan R.J. Iwamoto Y. Marinelli B. Gorbatov R. et al.Origins of tumor-associated macrophages and neutrophils.Proc. Natl. Acad. Sci. USA. 2012; 109: 2491-2496Crossref PubMed Scopus (456) Google Scholar). In a second approach, we transferred donor EYFP+ hematopoietic progenitor cells into cohorts of recipient animals in order to evaluate the capacity of a discrete cell population to produce TAMs in different in vivo conditions (Figure 4C). Analysis by flow cytometry on day 5 posttransfer showed that donor progenitor cells produced splenic monocytes and TAMs in tumor-bearing KP mice, as expected (Figure 4D). However, enalapril administration in KP mice decreased the production of these cells to levels found in tumor-free controls (Figure 4D). We further investigated enalapril’s impact on the TAM response by artificially limiting the drug’s action to the spleen. Specifically, EYFP− recipient KP mice (not treated with enalapril) received spleens transplanted from EYFP+ KP donor mice, some of which that were previously treated with enalapril (Figure 4E). The procedure allowed us to track EYFP+ splenocytes that relocated into the recipient (Swirski et al., 2009Swirski F.K. Nahrendorf M. Etzrodt M. Wildgruber M. Cortez-Retamozo V. Panizzi P. Figueiredo J.L. Kohler R.H. Chudnovskiy A. Waterman P. et al.Identification of splenic reservoir monocytes and their deployment to inflammatory sites.Science. 2009; 325: 612-616Crossref PubMed Scopus (1573) Google Scholar). Donor spleens were extensively perfused before transplantation to avoid exposing recipient mice to the drug. Analysis at 24 hr posttransplantation showed that enalapril-treated spleens contributed significantly fewer EYFP+ TAMs than their control counterparts (Figure 4F). Taken together, the above findings indicate that short-term blockade of AngII production restrains TAM progenitor amplification in the spleen. Furthermore, enalapril treatment likely did not trigger direct anti-tumor effects in KP mice because tumor cells derived from these mice remained fully able to expand in presence of high dose enalapril in vitro (Figure S4). Following the short-term results reported above, we investigated the impact of uninterrupted, extended enalapril treatment of KP mice. KP mice received daily enalapril over 3 weeks starting at week 8 after tumor initiation. This dose is well tolerated in vivo (Leuschner et al., 2010Leuschner F. Panizzi P. Chico-Calero I. Lee W.W. Ueno T. Cortez-Retamozo V. Waterman P. Gorbatov R. Marinelli B. Iwamoto Y. et al.Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction.Circ. Res. 2010; 107: 1364-1373Crossref PubMed Scopus (174) Google Scholar). Controls included untreated KP mice, KP mice that received hydralazine (to monitor the effects of low blood pressure triggered by enalapril treatment), and tumor-free controls. Evaluation in week 11 showed that enalapril treatment restrained tumor-induced HSC and MDP responses in the spleen but not in bone marrow, whereas treatment with hydralazine had no effect (Figure 5 A). Enalapril" @default.
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