Abstract
Cov roj (cholesterol).metabolism plays lub luag haujlwm tseem ceeb hauv kev ua haujlwm thiab polarization ntawm macrophages, cov pej xeem heterogeneous ntawm lub cev tiv thaiv kab mob nrog ntau lub luag haujlwm hauv kev mob qog noj ntshav. Tsab ntawv xov xwm no tshawb txog qhov kev nkag siab tam sim no ntawm yuav ua li cas cov roj cholesterol metabolism tswj cov lus teb ntawm macrophage-mediated antitumor, qhia txog cov tswv yim kho mob.
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Taw qhia
Cov roj (cholesterol) metabolism yog cov txheej txheem lom neeg uas cuam tshuam nrog kev sib txuas, thauj, khaws cia, thiab degradation ntawm cov cholesterol hauv lub cev. Cov roj (cholesterol) yog ib qho tseem ceeb lipid molecule uas ua haujlwm raws li cov txheej txheem ntawm cov cell membranes thiab yog ib qho ua ntej rau kev sib txuas ntawm ntau yam tshuaj hormones, kua tsib acids, thiab vitamin D.
Feem ntau ntawm cov roj (cholesterol) hauv lub cev yog synthesis nyob rau hauv daim siab thiab cov hnyuv, nrog rau lub siab yog lub hauv paus ntawm synthesis. Lub synthesis ntawm cov roj (cholesterol) pib nrog kev hloov pauv ntawm acetyl-CoA, ib qho khoom los ntawm cov metabolism hauv cellular, rau hauv 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Cov tshuaj tiv thaiv no yog catalyzed los ntawm enzyme HMG-CoA reductase, uas yog ib qho tseem ceeb tswj enzyme nyob rau hauv cholesterol synthesis.
Thaum ua ke, cov roj cholesterol tau thauj mus thoob lub cev hauv cov lipoprotein hais. Cov chav kawm tseem ceeb ntawm lipoproteins yog high-density lipoprotein (HDL), low-density lipoprotein (LDL), thiab very-low-density lipoprotein (VLDL). HDL cov khoom thauj cov roj cholesterol los ntawm cov ntaub so ntswg rov qab mus rau lub siab rau kev tso tawm, thaum LDL thiab VLDL cov khoom thauj cov roj cholesterol los ntawm lub siab mus rau cov ntaub so ntswg.
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Cov roj (cholesterol) metabolism hauv Macrophages
Macrophages vam khom cov roj cholesterol rau daim nyias nyias biogenesis, teeb liab, thiab cytokine ntau lawm. Cov roj (cholesterol) tuaj yeem raug tsim los ntawm endogenously lossis tau txais los ntawm ib puag ncig los ntawm cov khoom siv scavenger. Qhov sib npaug ntawm cov cholesterol synthesis thiab efflux yog nruj tswj hwm los ntawm ntau yam enzymes thiab thauj, suav nrog 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) thiab ATP-binding cassette transporters (ABCs).
Lub luag haujlwm ntawm Cholesterol Metabolism hauv Macrophage Polarization
Macrophage polarization ntawm M1 (classically activated) los yog M2 (alternately activated) phenotype yog cuam tshuam los ntawm cov roj cholesterol metabolism. M1 macrophages, tus cwj pwm los ntawm kev tsim cov cytokine siab, xav tau cov roj cholesterol kom pom kev ua haujlwm. Hloov pauv, M2 macrophages, uas txhawb cov qog loj hlob thiab angiogenesis, cuam tshuam nrog nce cov roj cholesterol.
Cholesterol Metabolism thiab Macrophage-Mediated Antitumor Teb
Cov ntaub ntawv pov thawj qhia tau hais tias kev hloov pauv cov roj cholesterol tuaj yeem ua rau macrophage polarization ntawm cov tshuaj tiv thaiv kab mob phenotype. Piv txwv li, inhibiting cholesterol synthesis los ntawm HMGCR inhibitors txhawb M1 polarization thiab txhim kho macrophage-mediated qog tua. Conversely, stimulating cholesterol efflux los ntawm upregulating ABC transporters nyiam M2 polarization thiab qog hlav.
Cov tswv yim kho mob Targeting Cholesterol Metabolism
Ntau cov tswv yim kho mob tsom rau cov roj cholesterol metabolism hauv macrophages tau tshawb nrhiav rau kev kho mob qog noj ntshav. Cov no suav nrog kev siv HMGCR inhibitors los txhawb cov qog nqaij hlav M1 polarization, nrog rau kev txhim kho cov tshuaj tshiab uas txhawb nqa cov roj cholesterol thiab inhibit qog-txhim kho M2 polarization.
Kev tshawb fawb tshiab
Thaum lub Plaub Hlis 19, Wang Hongyan cov kev tshawb fawb pab pawg ntawm Center for Excellence nyob rau hauv Molecular Cell Science, Suav Academy ntawm Sciences, koom tes nrog Shanghai University, Fudan University thiab Shanghai Jiao Tong University, luam tawm ib daim ntawv hauv internet hu ua 25-Hydroxycholesterol regulates lysosome. AMP kinase activation thiab metabolism hauv Immunity. Cov ntaub ntawv tshawb fawb ntawm reprogramming los qhia txog kev tiv thaiv kab mob macrophages. Txoj kev tshawb no nrhiav pom cov roj cholesterol tseem ceeb metabolism enzyme CH25H thiab cov metabolite 25-HC uas inhibit inflammatory macrophage activation, muab lub hom phiaj tshiab metabolic rau qog immunotherapy target macrophages, thiab tawm tswv yim ib txoj hauv kev rau reprogramming cov roj cholesterol metabolism los tswj innate tiv thaiv kab mob. tau txais kev nkag siab tshiab.
Hauv kev teb rau cov kab mob pathogenic microbial, macrophages tuaj yeem tso cov cytokines thiab interferons kom tshem tawm cov kab mob. Lawv tuaj yeem teb rau qhov kev txhawb nqa ntawm cov qog microenvironment lossis cytokine IL-4/IL-13 thiab nthuav tawm cov tshuaj tiv thaiv cytokines thiab arginase (Arg1) kom haus arginine hauv microenvironment thiab thaiv T cell proliferation thiab qog. tua ua haujlwm. Cov roj (cholesterol) metabolites yog cov khoom tseem ceeb ntawm cov cell membranes thiab organelle daim nyias nyias thiab tuaj yeem tswj cov cell proliferation, migration, o thiab lwm yam dej num, thaum cov roj cholesterol yog txuam nrog ntau yam kab mob. Yav dhau los, cov kev tshawb fawb pom tau hais tias cov tsub zuj zuj ntawm 7-dehydrocholesterol tuaj yeem txhawb kev tsim tawm ntawm hom I interferon, uas cuam tshuam rau kev ua haujlwm ntawm cov roj cholesterol inhibiting interferon. Cov roj (cholesterol) yog oxidized los tsim 25-hydroxycholesterol (25-HC); nyob rau hauv lem, 25-HC yog oxidized los tsim 7a, 25-hydroxycholesterol. 25-HC thiab 7a,{13}}hydroxycholesterol tau nce siab hauv cov ntshav peripheral ntawm cov neeg mob uas muaj kab mob autoimmune systemic lupus erythematosus (SLE). 7a,25-hydroxycholesterol txo qhov pib ntawm SLE los ntawm kev khi rau thiab ua kom cov G protein-coupled receptor EBI2 ntawm qhov chaw ntawm macrophages, inhibiting kev qhia ntawm ntau yam chemokines thiab inflammatory yam. Txawm li cas los xij, yuav ua li cas cov roj cholesterol metabolism tswj cov kev tiv thaiv kab mob thiab cov txheej txheem molecular ntawm cov qog nqaij hlav macrophages (TAMs) tseem tsis meej.
Pab neeg no tau siv peb hom kev tiv thaiv kab mob macrophages, uas yog M2 macrophages txhawb nqa los ntawm cytokines IL-4 thiab IL-13, macrophages incubated nyob rau hauv nruab nrab ntawm lub siab mob qog noj ntshav kab mob Hepa{3}}, thiab cov qog nqaij hlav. cov ntaub so ntswg. Cov kev txheeb xyuas TAMs tau raug tshuaj xyuas rau qhov qhia txog qib ntawm cov roj cholesterol metabolism enzymes, thiab nws tau pom tias cov roj (cholesterol) 25-hydroxylase (CH25H) raug ntxias kom nthuav tawm ntau heev. Cov kev tshawb fawb yav dhau los tau lees paub tias kev kis kab mob txhawb nqa qhov kev qhia siab ntawm CH25H thiab oxidizes cov roj cholesterol mus rau 25-HC, yog li thaiv tus kab mob los ntawm kev cuam tshuam cov tswv tsev cell los ntawm daim nyias nyias fusion. Txoj kev tshawb no pom tau nce qib ntawm oxysterol 25-HC hauv M2 macrophages, TAMs, thiab qog nqaij hlav. Los ntawm kev txheeb xyuas cov ntaub ntawv luam tawm, scRNA-seq pom tias CH25H tau qhia ntau heev hauv MARCO+TAMs lossis LYVE1+TAMs nyob rau hauv ntau hom qog nqaij hlav thiab muaj kev cuam tshuam tsis zoo nrog cov kev mob tshwm sim ntawm cov neeg mob qog.
Tsis tas li ntawd, cov kev tshawb fawb tau pom tias lactic acid nyob rau hauv cov qog microenvironment tuaj yeem ua rau Ch25h thiab cytokine IL-4/IL-13 tswj Ch25h transcription los ntawm qhov transcription factor STAT6. Cov khoom sib sau 25-HC khaws cia hauv macrophage lysosomes thiab sib tw nrog cov roj cholesterol los khi rau lysosome-localized signaling protein GPR155 los inhibit mTORC1 ua kom. Los ntawm kev txhim kho qhov ua kom muaj zog ntawm AMPKa, qhov kev hloov pauv ntawm STAT6 yog phosphorylated ntawm serine 564 los txhim kho cov kev ua haujlwm ntawm STAT6 thiab txhawb cov macrophages los tsim ntau Arg1 thiab cov tshuaj tiv thaiv. Hauv macrophages, khob tawm Ch25h tuaj yeem thim rov qab qhov kev tiv thaiv kab mob ntawm TAM thiab thaiv kev txhim kho ntawm ntau cov qog subcutaneous, nrog rau kev txhim kho T cell infiltration thiab ua kom muaj zog thiab kev qhia siab ntawm lub cev tiv thaiv kab mob PD-1 hauv cov ntaub so ntswg. Yog li, kev sib xyaw ntawm anti-PD1 monoclonal antibodies tuaj yeem txhim kho cov nyhuv tiv thaiv qog.
Hauv cov ntsiab lus, lub hom phiaj ntawm cov roj cholesterol oxidase CH25H txhawb kev hloov pauv ntawm "mob khaub thuas" rau hauv "kub qog" thiab sib txuas cov tshuaj tiv thaiv kab mob txhawm rau txhim kho qhov ua tau zoo ntawm cov qog tiv thaiv kab mob. Pab neeg no tau npaj lub tswv yim ntawm kev nrhiav oxysterols thiab cov roj cholesterol hauv lysosomes thiab qhov sib npaug ntawm ob los tswj txoj hmoo macrophage. Nyob rau tib lub sijhawm, lawv tau nthuav dav cov roj cholesterol oxidase CH25H thiab oxysterol 25-HC los ntawm kev kis kab mob mus rau thaj chaw kho mob qog noj ntshav.
Xaus
Cov roj cholesterol metabolism ua lub luag haujlwm tseem ceeb hauv kev tswj hwm macrophage polarization thiab ua haujlwm hauv kev mob qog noj ntshav. Los ntawm kev tsom mus rau cov roj cholesterol metabolism, peb tuaj yeem siv cov tshuaj tiv thaiv kab mob ntawm macrophages thiab tsim cov tswv yim kho tshiab rau kev kho mob qog noj ntshav. Kev tshawb fawb yav tom ntej yuav tsum tsom mus rau elucidating cov txheej txheem molecular hauv qab cov roj cholesterol-mediated macrophage polarization thiab tshawb nrhiav qhov chaw kho mob ntawm cov roj cholesterol metabolism-kev kho mob.