Brief Report
PHAGOCYTES,GRANULOCYTES,AND MYELOPOIESIS
Lysophosphatidic acid converts monocytes into macrophages in both mice and humans
Rashmi Ray 1,2and Vivek Rai 1
1
Department of Infectious Disease Biology,Institute of Life Sciences (An Autonomous Institute of Department of Biotechnology New Delhi),Bhubaneswar,India;and 2School of Life Sciences,Manipal University,Manipal,Karnataka,India
Monocytes and macrophages represent critical arms of the innate immune system and are considered regulators and effectors of inflammation and the innate immune response.
Monocytes can mobilize from bone marrow,traffic to their required destination,and
differentiate into effector cells,depending on the local tissue environment,to perform multiple roles during infection or inflammation,making them important components of body’s immune defense.Macrophages have diverse roles in tissue homeostasis,development,and tissue repair following injury.Adult bone marrow monocytes can give
rise to tissue-resident macrophages during infection or inflammatory reactions,besides
self-replication of tissue resident macrophages.Lysophosphatidic acid (LPA),a lipid by-product of autotaxin activity,is involved in cancer,vascular defects,and neural tissue,but is largely unexplored in immune system.Here,we reveal an unexpected function of LPA that transfigures CD11b 1murine monocytes into F4/801macrophages.LPA-stimulated Akt/mTOR signaling is critical for LPA-mediated macrophage development in mice.Additionally,transcriptome analysis reveals that PPAR g is the key transcriptional regulator in the development of LPA-induced macrophages.In humans,LPA mediates macrophage formation following similar pathways.These findings identify a critical role for LPA in regulating innate immune system.(Blood .2017;129(9):1177-1183)
Introduction
Monocytes and macrophages constitute important components of the mononuclear phagocytic system and play diverse roles during infection,in ?ammation,and tissue injury and repair.Monocytes differentiate into macrophages following stimulation with cyto-kines and/or microbial molecules.1,2Macrophages play a central role in the maintenance of tissue homeostasis,development,restoration after injury as well as the initiation and resolution of innate and adaptive immunity.Although macrophages were long considered to be derived from differentiation of bone marrow (BM)monocytes,recent studies have proved that tissue-resident macrophages are derived from yolk sac macrophages 3and fetal liver macrophages,4can self-replicate from local proliferation,5and do not solely depend on adult BM monocytes.However,during homeostatic adaptations,injury and in ?ammation macrophages of different phenotypes can be recruited from the monocyte reservoirs of blood,spleen,and BM.6,7Lysophosphatidic acid (LPA),a bioactive phospholipid,exerts numerous cell responses,including cell motility,neuropathic pain,infertility,cardiovascular disease,in ?ammation,?brosis,and cancer.8-10This diversity is mediated by broad and overlapping expression patterns and multiple downstream signaling pathways activated by identical LPA receptors,but this lipid molecule remains little known in the immune system.9,11-14Here we reveal that LPA,a small lipid molecule,converts monocytes into macrophages in both mice and humans.
Study design
Monocytes were isolated from the BM of C57BL/6mice using negative selec-tion of mouse monocytes (CD11b 1)via magnetic beads from Stem Cell Technologies.Isolated BM monocytes were incubated in the presence of LPA,macrophage colony-stimulating factor (M-CSF),and Akt,mTor,or PPAR g inhibitors for the indicated periods and harvested for ?ow cytometry,gene expression,or immunoblotting analyses (for details,see supplemental Methods,available on the Blood Web site).
Results and discussion
To explore the role of LPA on monocytes,we added LPA on CD11b 1monocytes isolated from the BM of 6-to 8-week-old C57BL/6mice and observed them after 5days.To our surprise,we found that the monocytes had survived and phenotypically been converted into a different cell type.Giemsa staining revealed their morphology was similar to that of macrophages (Figure 1A-B).F4/80is one of the most speci ?c cell-surface markers for murine macrophages.15-18Our immunoblot,immuno ?uorescence,and ?ow cytometry analysis showed F4/80expression in these macrophages (Figure 1B-D;supplemental Figure 1E),con ?rming that these cells were macro-phages.Quantitative polymerase chain reaction (qPCR)analysis showed increased expression of F4/80and CD11b surface markers in
Submitted 3October 2016;accepted 23December 2016.Prepublished online as Blood First Edition paper,9January 2017;DOI 10.1182/blood-2016-10-743757.
The online version of this article contains a data supplement.
The publication costs of this article were defrayed in part by page charge payment.Therefore,and solely to indicate this fact,this article is hereby marked “advertisement”in accordance with 18USC section 1734.?2017by The American Society of Hematology
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Figure 1.LPA converts murine monocytes into macrophages via the Akt-mTor pathway.(A)Representative phase contrast images of mouse monocytes cultured in RPMI only (control [ctrl])or in RPMI with LPA (10m M)or M-CSF (10ng/mL)for up to 7days.(B)Upper panel:Giemsa-stained images of mouse monocytes cultured in vitro in the presence of LPA or M-CSF for 7days.Figures are representative of 10images (n 510).Lower panel:Immunoblot showing levels of F4/80and b-actin in control (RPMI),LPA,and M-CSF–treated monocytes.(C)FACS plots showing proportion of CD11b 1and F4/801macrophages in monocytes treated with LPA or M-CSF for 5days.(D)Quantification of percentage of CD11b 1and F4/801cells in monocytes cultured in medium and cells cultured in medium with LPA or M-CSF.(E-F)Quantification of CD11b-and F4/80-relative mRNA in monocytes (control)and in monocytes cultured for 5days in medium with different doses of LPA (50and 10m M)or M-CSF.(G-H)Immunoblot showing levels of p -Akt,p -mTor,Akt,and mTor in macrophages differentiated from mouse monocytes cultured in medium with LPA at indicated time (t)points.(I)Representative Giemsa-stained images of LPA-derived macrophages or M-CSF–derived macrophages without or with pretreatment of Akt inhibitor (LY-294002[Ly]).(J)FACS plots showing the proportion of CD11b 1and F4/801macrophages in monocytes cultured in the presence of LPA,M-CSF,or LPS and monocytes pretreated with Akt inhibitor (LY-294002)and mTor inhibitor (rapamycin)and cultured in medium containing LPA,M-CSF,or LPS,respectively.(K)Quantification of CD11b 1and F4/801macrophages cultured in medium with only LPA and LPA after pretreatment with Akt or mTor inhibitor,respectively.Scale bars,100m m.Graph presents mean 6standard deviation (SD)of 5experiments per condition.Error bars represent SD.Student t test was used for all statistical analyses (***P ,.001,**P ,.01,*P ,.05).
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a dose-dependent manner in LPA-treated monocytes.M-CSF,a well-known macrophage-inducing growth factor,19-21was used as a positive control (Figure 1E-F;supplemental Figure 1A-B).Further-more,LPA-treated monocytes did not show much enhancement in the proliferation of differentiating F4/80macrophages (supplemental Figure 2D-E).To further check the effect of LPA on monocytes other than those of BM origin,we isolated and treated splenic monocytes with LPA and found that it induced macrophage formation in splenic-origin monocytes as well (supplemental Figure 1C-D).Immunoblot analysis for phosphorylated proteins showed increased phosphorylation of Akt in monocytes after LPA was added,with further downstream mTor phosphorylations (Figure 1G-H;supplemental Figure 2A).To con ?rm the involvement of the Akt/mTor pathway in LPA-mediated macrophage formation,we pretreated mouse mono-cytes with a speci ?c Akt inhibitor (LY294002)and added LPA to these monocytes to convert them into macrophages.Morphological observation indicated reduced formation of macrophages after Akt inhibitor pretreatment (Figure 1I;supplemental Figure 2B-C).FACS
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analysis showed a drastic reduction in the percentage of F4/80-expressing cells in LPA-treated monocytes,but did not affect macrophage formation from M-CSF or lipopolysaccharide (LPS)at a similar dose (Figure 1J-K).Mouse monocytes pretreated with mTor inhibitor (rapamycin)followed by the addition of LPA,M-CSF,or LPS showed no signi ?cant effect on M-CSF –mediated macrophage
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Figure 2.LPA generates macrophages in vivo and in humans through a common transcription factor,PPAR g ,both in mice and humans.(A)FACS plots showing percentage of CD11b 1and F4/801macrophages elicited in peritoneal and pleural cavities of C57BL/6mice injected with 3%thioglycollate in the absence or presence of 20m g LPA.PBS,phosphate-buffered saline.(B)FACS plots showing percentage of CD11b 1and F4/801macrophages elicited in peritoneal and pleural cavities of FVB (FVB-WT)and FVB-ATX-Tg mice injected with 3%thioglycollate.(C)Proportion of peritoneal macrophages positive for F4/80CD11b in FVB WT and FVB ATX-Tg mice.(D)Heat map showing the expression of surface markers,transcription factors,and cytokine-related genes in monocytes (Mo)and LPA-derived macrophages (LDMa).(E)Quantification of PPAR g mRNA in mouse monocytes and macrophages derived from LPA or M-CSF–treated mouse monocytes for different days.(F)FACS plots showing percentage of CD11b and F4/80macrophages in monocytes pretreated with different doses of PPAR g inhibitor and cultured in the presence of LPA or M-CSF for 5days.(G)Quantification of PPAR g in monocytes (control),monocytes treated with LPA,and monocytes pretreated with Akt inhibitor or mTor inhibitor and cultured further in medium supplemented with LPA for 5days.Rap,rapamycin.(H)Representative phase contrast and Giemsa-stained images of human monocytes cultured in RPMI only (control)and human monocytes cultured in medium with 2.5m M LPA and 10ng/mL M-CSF for 7days.(I-K)Quantification of CD14,CD68,and CD206mRNA in human monocytes and macrophages derived from human monocytes cultured with different doses of LPA or M-CSF at day 5.(L)FACS plots showing percentage of CD141and CD681macrophages in monocytes treated with M-CSF,LPA,or Akt inhibitor (LY294002)-pretreated monocytes cultured in medium with LPA for 5days.(M)Quantification of PPAR g -relative mRNA in human monocytes and monocytes cultured in medium with LPA or M-CSF for 7days.(N)FACS plots showing percentage of CD141and CD681macrophages in human monocytes cultured with or without PPAR g inhibitor in the presence of LPA for 5days.Graphs depict mean 6SD of 4or 5mice.Data are representative of 2independent experiments.Error bars represent SD.Scale bars,100m m.Student t test was used for all statistical analyses (***P ,.001).
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formation,whereas it inhibited macrophage formation in LPA-treated monocytes at a similar dose (Figure 1J;supplemental Figure 2C).Thioglycollate injection in the pleural and peritoneum cavities elicits a higher number of monocytes from circulation.5,22,23C57BL/6mice were injected with 3%thioglycollate in the peritoneum and pleural cavities followed by LPA injection in the same cavities.The total cell population was isolated from the peritoneal and pleural cavities 3days later and showed a higher percentage of F4/80-expressing cells in LPA-
injected mice compared with phosphate-buffered saline –injected mice both in the peritoneum and pleural cavities (Figure 2A),con ?rming that LPA converts monocytes into macrophages in vivo.
LPA is synthesized from lysophosphatidylcholine by the catalytic activity of autotaxin (Atx)in biological systems.9,24To validate our ?nding with conditional Atx transgenic (ATX-Tg)mice,which pro-duce more LPA because of a higher Atx expression in the circulation,25we injected 3%thioglycollate in the peritoneal and pleural cavities
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wild-type(FVB WT)and FVB ATX-Tg mice.Our analysis showed a higher percentage of F4/80-expressing cells in ATX-Tg mice compared with WT mice(Figure2B-C).
RNA sequencing of isolated monocytes and LPA-converted macrophages was performed.Supplemental Figure4A highlights a set of genes whose expression distinguishes between monocytes and LPA-mediated macrophages;6biological categories with the predicted functionality of each subset are spotlighted(Figure2D;supplemental Figure4B-E).F4/80(EMR1)was highly expressed in LPA-converted macrophages,along with PPAR g transcription factor(TF)as revealed by network analysis suggesting PPAR g is a“master”TF for LPA-mediated macrophages(supplemental Figure4F).
qPCR con?rmed higher expression of PPAR g along with macrophage-speci?c TFs(Figure2E;supplemental Figure5A-B). Further,chromatin immunoprecipitation-qPCR analysis revealed measurable recruitment of endogenous PPAR g at the PPAR g-binding sites26in LPA-derived macrophages compared with control monocytes (supplemental Figure5C).PPAR g inhibition drastically reduced the macrophage population(Figure2F;supplemental Figure6A).In-terestingly,Akt or mTor inhibitor pretreatment reduced PPAR g expression during LPA-mediated monocyte differentiation to macro-phages(Figure2G).To check the functional implication of these macrophages,we stimulated LPA-derived macrophages with LPS and found elevated levels of cytokines and chemokine secretion similar to M-CSF–derived macrophages(supplemental Figure7A-F).
To determine whether murine development of macrophages from monocytes were coherent with the LPA effect on human monocytes, CD141monocytes isolated from human peripheral blood mononuclear cells were treated with different doses of LPA.These LPA-generated macrophages showed a higher expression of CD68,as seen by?ow cytometry and CD14,CD64,CD68,and CD206via qPCR,comparable to human M-CSF–generated macrophages(Figure2H-L;supplemental Figure6B).Further qPCR showed that2.5m M LPA was optimum for human macrophage formation,with higher expression of CD68,a macrophage marker,and CD14(supplemental Figure9A-B).To further con?rm the Akt/mTor pathway found in LPA-mediated mouse macrophage formation in human macrophage formation from CD14 monocytes,we pretreated CD14monocytes with Akt inhibitor fol-lowed by the addition of LPA.We found that Akt inhibitor–treated CD14monocytes severely reduced the percentage of macrophages on further LPA treatments(Figure2L).qPCR analysis also con?rmed enhanced expression of PPAR g messenger RNA(mRNA)in human monocytes.Monocytes pretreated with PPAR g inhibitor did not form macrophages from CD14monocytes in the presence of LPA,con-?rming its role in human macrophage formation(Figure2M-N;supplemental Figure8A-B)and establishing PPAR g as the key master regulator in LPA-mediated macrophage development.
This work demonstrates the unique potential of LPA to produce macrophages ex vivo and in vivo and in both mice and humans. Macrophages are an important component of the innate immune system and produce a diverse range of biologically active molecules that participate in both bene?cial and detrimental outcomes in in?amma-tion.As a result,this makes LPA-mediated macrophages an important avenue for therapeutic interventions,and their products may open ways for controlling in?ammatory diseases.16,22Akt-mTor or PPAR g is critical in LPA-mediated macrophage formation and differentiation as seen in vitro and in vivo.Furthermore,transcriptome analysis charac-terizes these new LPA-mediated macrophages.
This?nding may ultimately provide a foundation for LPA in the innate system.Interestingly,in many types of cancer and tumors, LPA is highly upregulated.9,14,27This work facilitates a future possible role of LPA in tumor-associated macrophages,but a better understanding is needed of the underlying mechanisms for this reprogramming.
Acknowledgments
The authors thank Gordon Mills,MD Anderson Cancer Center, Houston,TX,for generously sharing ATX transgenic mice;Khokan Rana for his assistance in the animal studies;and Bioserve Bio-technologies,India,for help in sequencing and data analysis.
This work was supported by the Department of Biotechnology, New Delhi(grant102/IFD/SAN/2237)and the Institute of Life Sciences core fund.
Authorship
Contribution:R.R.contributed to project planning,experimental work,data analysis,and writing the manuscript;and V.R.contributed to project planning,data analysis,writing the manuscript,and overall supervision of this study.
Con?ict-of-interest disclosure:The authors declare no competing ?nancial interests.
ORCID pro?les:R.R.,0000-0002-4794-3124;V.R.,0000-0003-4539-8916.
Correspondence:Vivek Rai,Institute of Life Sciences (An Autonomous Institute of Department of Biotechnology New Delhi),Bhubaneswar-751023,India;e-mail:vivekrai.a@https://www.doczj.com/doc/bb17788086.html,.
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BLOOD,2MARCH2017x VOLUME129,NUMBER9MONOCYTES AND MACROPHAGES1183
online January 9, 2017
originally published doi:10.1182/blood-2016-10-7437572017 129: 1177-1183
Rashmi Ray and Vivek Rai
mice and humans
Lysophosphatidic acid converts monocytes into macrophages in both
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