Functional polarization of tumour-associated macrophages by tumour-derived lactic acid

Colegio, Oscar R.; Chu, Ngoc Quynh; Szabo, Alison L.; Chu, Thomas; Rhebergen, Anne Marie; Jairam, Vikram; Cyrus, Nika; Brokowski, Carolyn; Eisenbarth, Stephanie C.; Phillips, Gillian M.; Cline, Gary W.; Phillips, Andrew J.; Medzhitov, Ruslan

doi:10.1038/nature13490

Cited by 2,177 publications

(2,100 citation statements)

References 23 publications

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“…Using this model, we identified Arg1 expression in lung granulomas analogous to those in TB patients and in NHP models of TB (11,38). Arg1-expressing cells surrounded the necrotic, hypoxic center of caseous granulomas, suggesting the hypoxic environment in this region potentially contributes to Arg1 induction (39,40,(47)(48)(49). As reported in human and NHP TB granulomas (11,38), inflammatory macrophages were the major cellular population expressing Arg1 in TB lung granulomas of Nos2 −/− mice.…”

Section: Discussionmentioning

confidence: 64%

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

Duque-Correa¹,

Kühl

Rodríguez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

109

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Lung granulomas develop upon Mycobacterium tuberculosis (Mtb) infection as a hallmark of human tuberculosis (TB). They are structured aggregates consisting mainly of Mtb-infected and -uninfected macrophages and Mtb-specific T cells. The production of NO by granuloma macrophages expressing nitric oxide synthase-2 (NOS2) via L-arginine and oxygen is a key protective mechanism against mycobacteria. Despite this protection, TB granulomas are often hypoxic, and bacterial killing via NOS2 in these conditions is likely suboptimal. Arginase-1 (Arg1) also metabolizes L-arginine but does not require oxygen as a substrate and has been shown to regulate NOS2 via substrate competition. However, in other infectious diseases in which granulomas occur, such as leishmaniasis and schistosomiasis, Arg1 plays additional roles such as T-cell regulation and tissue repair that are independent of NOS2 suppression. To address whether Arg1 could perform similar functions in hypoxic regions of TB granulomas, we used a TB murine granuloma model in which NOS2 is absent. Abrogation of Arg1 expression in macrophages in this setting resulted in exacerbated lung granuloma pathology and bacterial burden. Arg1 expression in hypoxic granuloma regions correlated with decreased T-cell proliferation, suggesting that Arg1 regulation of T-cell immunity is involved in disease control. Our data argue that Arg1 plays a central role in the control of TB when NOS2 is rendered ineffective by hypoxia.

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Section: Discussionmentioning

confidence: 64%

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

Duque-Correa¹,

Kühl

Rodríguez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

109

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“…47 Apart from angiogenesis, hif-1a has been shown to regulate EMT, cell cycle, 48 and macrophage polarization. 24 Recent studies have shown that hif-1a can mediate the effects of tumor-derived lactic acid 49 and cytokines (Oncostatin M and Eotaxin) 50 to promote M2 phenotype in tumor microenvironment. Given this recently reported role of hif-1a in macrophage polarization and our findings in hepatocytes here, we speculated that hif-1a in hepatocytes may be crucial in polarizing macrophages in HCC microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

et al. 2016

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Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat-high cholesterol-high sugar diet (HF-HC-HSD). We assessed liver MRI and histology, serum ALT, AFP, liver triglycerides, and cytokines. Macrophage polarization was determined by IL-12/TNFa (M1) and CD163/ CD206 (M2) expression using flow cytometry. Role of hif-1a-induced IL-10 was dissected in hepatocyte specific hif-1aKO and hif-1adPA (over-expression) mice. The western diet-induced features of NASH and accelerated HCC development after carcinogen exposure. Liver fibrosis and serum AFP were significantly increased in DEN C HF-HC-HSD mice compared to controls. Western diet resulted in macrophage (F4/ 80 C CD11b C ) infiltration to liver and DEN C HF-HC-HSD mice showed preferential increase in M2 macrophages. Isolated hepatocytes from western diet fed mice showed significant upregulation of the hypoxia-inducible transcription factor, hif-1a, and livers from hif-1a over-expressing mice had increased proportion of M2 macrophages. Primary hepatocytes from wild-type mice treated with DEN and palmitic acid in vitro showed activation of hif-1a and induction of IL-10, a M2 polarizing cytokine. IL-10 neutralization in hepatocyte-derived culture supernatant prevented M2 macrophage polarization and silencing hif-1a in macrophages blocked their M2 polarization. Therefore, our data demonstrate that NASH accelerates HCC progression via upregulation of hif-1a mediated IL-10 polarizing M2 macrophages.

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“…This meta bolic shift sup ports im muno sup pres sion and tu mor growth [101]. In ad di tion, lac tate taken up by TAMs ac ti vates the tran scrip tion of VEGF and L argi nine me tab o liz ing en zyme arginase 1 (ARG1) genes through HIF 1α sta bi liza tion [102,104,105]. Over ex pres sion of VEGF and ARG1 by TAMs sus tains tu mor growth and tis sue re mod el ing [104], as well as im mune es cape [106].…”

Section: Metabolic Cooperation In Cancermentioning

confidence: 99%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

173

139

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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Functional polarization of tumour-associated macrophages by tumour-derived lactic acid

Cited by 2,177 publications

References 23 publications

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

Cancer metabolism in space and time: Beyond the Warburg effect

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