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F6. Inflamasom - Biologija

F6. Inflamasom - Biologija


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Ljeto 17 Razmislite o stvarima od kojih biste željeli da vas vaš imunološki sustav zaštiti. I naravno, želite biti zaštićeni od sebe tako što ne želite aktivirati svoj imunološki sustav vlastitim antigenima. Ali što je s "nebiološkim" molekulama poput silicijevog dioksida ili azbesta čija bi prisutnost mogla biti štetna? Što je s normalnim biomolekulama (proteini, nukleinske kiseline) koje se iznenada nađu na pogrešnom staničnom mjestu zbog stanične smrti nekrozom ili fizičke ozljede?

U prethodnom odjeljku raspravljali smo o tome kako urođene stanice imunološkog sustava (dendritske stanice, makrofagi, eozinofili, itd.) imaju receptore koji prepoznaju zajedničke molekularni obrasci povezani s patogenom (PAMP) kao što su lipopolisakahridi (LPS) na površini bakterija, manoza na bakterijama i kvascu, flagelin iz bakterijskih flagela, dsRNA (iz virusa) i nemetilirani CpG motivi u bakterijskoj DNK. Ove antigene prepoznaju receptori za prepoznavanje uzoraka (PRR) – točnije Receptori slični naplati (TLR) 1-10 (prikaz, stručni). To uključuje TLR plazma membrane (TL4 za LPS, TL5 za flagelin, TLR 1, 2 i 6 za komponente membrane i stijenke gljivica i bakterija) i intracelularne endosomske TLR (TLR3 za dsRNA, TLR 7 i 8 za ssRNA i TLR9 za dsDNA)

Molekularni obrasci povezani s oštećenjem (DAMP) obično se nalaze na molekulama koje se oslobađaju iz stanice ili unutarstaničnih odjeljaka pri staničnom oštećenju (otuda naziv DAMP). Mnogi su nuklearni ili citoplazmatski proteini koji se oslobađaju iz stanica. Oni bi se sada našli u oksidirajućem okruženju što bi dodatno promijenilo njihova svojstva. Uobičajeni DAMP proteini uključuju proteine ​​toplinskog šoka, histone i proteine ​​skupine visoke pokretljivosti (i nuklearne) i proteine ​​citoskeleta. Razmislite koje bi se ne-proteinske molekule mogle osloboditi iz oštećenih stanica koje bi mogle predstavljati probleme? Evo nekih drugih uobičajenih neproteinskih DAMP-ova: ATP, mokraćna kiselina, heparin sulfat, DNK i kristali kolesterola. Na pogrešnom mjestu, to se može smatrati signalima opasnosti.

Ako TLR prepoznaju PAMP-ove, što prepoznaje DAMP-ove? Prepoznaje ih druga vrsta intracelularnog receptora za prepoznavanje uzoraka (PRR) tzv NOD (Vezivanje nukleotida Oligomerizacija Domain (NOD)- Like Receptori ili NLR-ovi. NLR-ovi također prepoznati PAMP-ove. Proteini su također nazvani kao Nukleotid-vezujuća domena (NBD) i Leucine-Rich repeat (LRR) – koji sadrže proteine ​​(NLR)s. Ova obitelj proteina sudjeluje u formiranju velike proteinske strukture zvane inflamazom. (Oprostite zbog višestrukih kratica i sustava imenovanja!)

Budući da i PAMP i DAMP predstavljaju opasnosti, bilo bi logično da nakon što prepoznaju svoje srodne PRR (TLR i NLR, respektivno), da se putevi koji vode od okupiranih receptora mogu konvergirati u zajednički efektorski sustav za oslobađanje upalnih citokina iz imunoloških stanica. S obzirom da bi nekontrolirano oslobađanje imunološkog efektora iz stanica u upalnom odgovoru moglo biti opasno, ponekad bi bilo korisno zahtijevati dva signala za pokretanje oslobađanja citokina iz stanice. Vidjeli smo ovaj zahtjev za dva signala za aktivaciju T stanica.

Dva takva upalna citokina su interleukin 1-beta (IL 1-b) i IL-18. Aktivacija TLR-a pomoću PAMP-a dovodi do aktivacije moćnog faktora transkripcije imunoloških stanica, NF-kbeta, što dovodi do transkripcije gena za prekursor citokina, pro-interleukina 1-beta. Bez specifičnog proteolitičkog cijepanja, aktivni citokin se neće osloboditi iz stanice.

Proteaza potrebna za ovo cijepanje aktivira se signalom koji nastaje kada DAMP aktivira NLR, koji zatim nizom interakcija dovodi do proteolitičke aktivacije druge neaktivne proteaze, prokaspaza 1, na velikom multiproteinskom kompleksu nazvanom inflamazom. (U kasnijim poglavljima vidjet ćemo druge takve proteinske komplekse s ciljanim aktivnostima - uključujući spliceosom, koji spaja RNA za proizvodnju mRNA i proteasom koji provodi kontroliranu intracelularnu proteolizu). Aktivirani inflamasom aktivira prokapazu za proizvodnju aktivnog proteina kaspaza (cistein-asparaginska proteaza).

Konvergencija signala iz PAMP aktivacije TLR i DAMP aktivacije NLD na inflammasomu prikazana je na donjoj slici.

Aktivni citokin interleukin 1-beta pomaže regrutirati urođene imunološke stanice na mjesto infekcije. Također utječe na aktivnost imunoloških stanica u adaptivnom imunološkom odgovoru (T i B stanice). Aktivni IL-18 dovodi do povećanja drugog citokina, interferona gama, a također povećava aktivnost T stanica koje ubijaju druge stanice.

Fokus ovog poglavlja je na obvezujućoj interakciji i njihovim biološkim posljedicama. Iz te perspektive, ovaj dio će se pozabaviti strukturom i aktivnošću kaspaza koje aktiviraju pro-citokin prointerleukin 1 beta, strukturom i ligandi za NLR, strukturom i svojstvima inflamasoma, i konačno kako "opasne" molekule kao što je ATP a kristali (kolesterol, silicij) aktiviraju inflamasom. Nažalost, postoji bezbroj proteina koji su povezani s ludim akronimima za imena. Ovi proteini imaju više domena i mnogi od proteina često imaju više imena. Oprostite unaprijed!

A. Kaspaze

Kaspaze (Cys-asp-proteaze), ne treba ih brkati s Cas9 (protein 9 povezan s CRISPR-om, RNA-vođena DNA endonukleaza) je proteaza koja kada je aktivna može dovesti do smrti stanice ili na manje strog način inicirati upalni odgovor (ponekad dobro, često loše ili čak fatalno). Imaju aktivno mjesto nukleofilnog Cys i cijepaju peptidne veze nakon Asp u ciljnim proteinima. Sve kaspaze (13 u ljudi) imaju N-terminalnu pro-domenu nakon koje slijede velike i male podjedinice katalitičke domene proteaze. Kao i kod drugih proteaza, nalazi se kao neaktivan zimogen. Zašto je ovo važno?

Da bi se aktivirali, regrutiraju se u protein skele gdje se aktiviraju uklanjanjem N-terminalne pro domene zymogena i zatim drugim rezom između velike i male katalitičke podjedinice. Enzim koji to čini je sama kaspaza u autokatalitičkom koraku. Postoje 3 vrste kaspaza, od kojih su dvije uključene u programiranu staničnu smrt. Razgovarat ćemo o obradi upalnih citokina Caspase-1. Nakon što se aktiviraju, inicijatori aktiviraju druge efektorske (dželatske) kaspaze u stanici). Kaspazu 1 aktivira inflamasom.

Dvije glavne domene nalaze se u kaspazi 1, domena regrutiranja kaspaze (CARD) koja posreduje u samointerakciji sa skelom i adapterskim proteinima u inflamasomu za aktivaciju i proteolitička katalitička domena, kao što je prikazano u nastavku. Sve strukture domene u odjeljku dobivene su korištenjem Conserved Domains od NCBI (https://www.ncbi.nlm.nih.gov/Structure/cdd/wrpsb.cgi) ili Simple Modular Architecture Research Tool (SMART) na EMBL-u (http://smart.embl-heidelberg.de/smart/set_mode.cgi?NORMAL=1). Uniprot je korišten za proteinske (FASTA) sekvence (http://www.uniprot.org/uniprot/). Često ćemo vidjeti domenu CARD.

B: NOD-ovi receptorski proteini (NLRP)

NLRP su obitelj proteina sa sličnom strukturom domene. Struktura domene od tri (NLRP1, 2 i 3) prikazana je u nastavku koristeći dva različita prikaza.

NLRP1, 2 i 3

Evo drugih malo drugačijih prikaza ova tri proteina:

NLRP1 (također se naziva NALP1)

NLRP3 (ILI NALP3)

NLRP4

Drugi protein u obitelji NLR je NAIP (protein inhibitora neuronske apoptoze). Struktura domene za NAIP1 prikazana je u nastavku. Za razliku od drugih NLR-a za koje još nisu pronađeni specifični ligandi, pokazalo se da nekoliko NAIP-ova veže specifične PAMP-ove. NAIP1 veže protein igle CprI iz C.violaceum koji počinje pokretati sklop NLRC4 inflamasoma. NAIP2 veže protein unutarnjeg štapića bakterijskog sustava sekrecije tipa III (koji za Salmonella typhimurium je protein PrgJ). NAIP5 i NAIP6 vežu bakterijski flagelin (koji za Salmonella typhimurium je protein FliC).

NAIP1

AAA je reprezentacija druge domene i označava aktivnosti povezane s ATP-om u stanici (inače označeno kao NACHT domena u gornjem prikazu).

NAIP2 stupa u interakciju s drugim adapterskim proteinom obitelji NLR, NLRC4 (protein koji sadrži domenu NLR obitelji CARD), kako bi formirao inflamasom. Struktura domene NAIP2 prikazana je u nastavku:

NAIP2:

Još jedan protein obitelji NLR uključen u formiranje inflamasoma je NLRC4 (protein 4 koji sadrži domenu NLR obitelji CARD)

NLRC4

Imajte na umu da mnogi od ovih proteina dijele zajedničke domene:

  • Pyrin-NALP - Pirinske domene na različitim proteinima se samopovezuju kroz međuproteinske interakcije Pyrin:Pryin
  • NACHT - Ova domena sadrži oko 300-400 aminokiselina i može vezati ATP i može ga cijepati (tj. djelovati kao ATPaza)
  • LRR - za Leucine Rich Repeat. Ovih 20-30 ponavljanja aminokiselina mogu se pojaviti do 45 puta u danom proteinu. Preklapaju se u oblik luka i čini se da olakšavaju interakcije proteina i proteina. Na konkavnoj strani luka imaju paralelni beta list dok na konveksnoj strani imaju alfa spiralu. Čini se da su također uključeni u vezanje PAMPS i DAMP-a;
  • KARTICA - za aktivaciju kaspaze i regrutiranje. CARD domene na različitim proteinima se samopovezuju kroz međuproteinske CARD:CARD interakcije;
  • BIR - Bakulovirusna inhibicija ponavljanja proteina apoptoze;
  • ASC – pjegasti protein povezan s apoptozom koji sadrži CARD Adapter domenu, dopuštajući mu interakciju s drugim proteinima s CARD domenom.

C. ASC adapterski protein

Mali adapterski proteini poput ASC s CARD domenom posreduju u vezivanju kaspaza u apoptozomu (uključenom u apoptozu ili programiranu smrt stanice) i u inflamasomu. Ovaj manji protein ima dvije domene, domenu pirina i domenu CARD. Potreban je za regrutiranje kaspaze-1 u neke inflamasome (na primjer, one koji sadrže NLRP2 i NLRP3

Inflammasome

Aktivni inflamasom se općenito sastoji od tri različite vrste proteina, od kojih su neki prisutni u više kopija: NLRP, adapterski proteini poput ASC i prokaspaze. Također mogu sadržavati dodatne proteine ​​za regrutiranje i senzore liganda. Raspravljat ćemo o dvije vrste koristeći različite NLRP-ove, NLRP4 i NLRP3 inflammasom.

a. NLRP4 Inflamasom

Trenutačno, najbolje strukturne informacije (dobivene kriomikroskopijom) su za NAIP2:NLRP4 inflammasom. Slike i Jsmol modeli u nastavku prikazuju dio kompleksa koji se sastoji od 11 NLRP4 podjedinica raspoređenih u velikom prstenu. Stvarni biološki kompleks ima 1 NAIP2 podjedinicu i 10 NLRP4.

Jmol: NAIP2-NLRC4 inflammasome (3jbl) Jmol14 (Java) | JSMol (HTML5)

Kako nastaje ova struktura? Vjerojatno ne bi postojao u odsutnosti PAMP-a ili DAMP-a kako bi se minimizirala imunološki posredovana upalna oštećenja. Podaci sugeriraju da se bakterijski protein PrgJ (označen kao PrgX na donjoj slici) veže na svoj receptor, NAIP2, mijenjajući njegovu konformaciju kao što je prikazano u nastavku. Ovaj binarni kompleks predstavlja asimetričnu elektrostatičku površinu koja omogućuje gubitak povezanosti s NLRP4, što dovodi, nakon konformacijske promjene, do čvršće interakcije vezanja. Još devet NLRP4 veže se na sličan način da tvori strukturu prstena od 11 podjedinica.

Komplementarne elektrostatičke interakcije između dva od mnogih monomera NLRC4 podjedinice u NLRP4 inflammasomu prikazane su na donjoj slici.

Gornja desna ploča prikazuje dva od NLRC 4 monomera (od 12 u modelu Jsmol) povezana jedan s drugim, s konkavnim unutarnjim licem A podjedinice u interakciji s konveksnim vanjskim licem B podjedinice. Radi jednostavnosti, istaknute su samo interakcije na vrhu dimera. Ostale ploče prikazuju površinu elektrostatičkog potencijala (crvena označava negativnu, a plava pozitivnu) za svaki monomer na kliznoj ljestvici od -5 do +5 (slike stvorene pomoću PDB2PQR poslužitelja i Pymola).

Prikazana vanjska površina negativnog (crvenog) elektrostatskog potencijala na jednom NLRC4 monomeru koji je komplementarna pozitivnoj (unutarnjoj) površini na drugoj NLRC4 podjedinici prikazana je na svakoj ploči crvenim ili plavim elipsama, redom. Zakrivljena tercijarna struktura proteina i suprotni elektrostatički površinski potencijali suprotnih strana čine podjedinice formiranjem velike prstenaste 12-merne jezgre nukleosoma.

Imajte na umu da ovaj sastavljeni prsten okuplja CARD (domena za regrutiranje kaspaze, žuti krugovi/sfere) koja može stupiti u interakciju s CARD domenom proteina prokaspase kroz interakcije CARD:CARD među proteinima (zamislite hrpu igraćih karata koje su sve zaglavljene u špil karata).

Jednom sklopljene, proksimalne prokaspaze autokatalitički pretvaraju prokapazu 1 u aktivnu kaspazu 1, koja proteolizom može aktivirati citokine interleukin 1 beta i interleukin 18 da tvore aktivne citokine koji se oslobađaju iz stanice. Zapamtite, procitokini su prisutni samo ako su njihovi geni transkribirani aktivacijom transkripcijskog faktora NF-kappa beta kroz PAMP vezanje na TLR.

B. NLRP3 inflamasomi

Za razliku od inflamasoma NLRP4 koji zahtijevaju definirani PAMP/DAMP za aktivaciju, čini se da se inflamasomi NLRP3 aktiviraju staničnim distresom kao i izlaganjem stanica patogenima. Jedan je od glavnih odgovora na razne mikrobne infekcije. S obzirom na veliki broj mikroba koji dovode do aktivacije inflamasoma NLRP3, sugerira se da je stvarni signal koji pokreće NLRP3 neizravan. Jedan takav neizravni signal je K+ razine iona u stanicama.

U normalnim stanicama, K+ ioni su viši u citoplazmi nego u vanjskoj strani stanice (vidi Poglavlje 9B: Neuralna signalizacija). Smanjenje kalijevih iona u stanicama uzrokovano efluksom može aktivirati inflamasome NLRP3. Ostali uvjeti uključuju rupturu lizosoma (možda povezano sa staničnim unosom čestica poput silicija, mokraćne kiseline, kristala kolesterola i drugih "nanočestica"), promijenjen metabolizam mitohondrija (što može dovesti do reaktivnih vrsta kisika unutar stanice) itd. Očito , svi ovi okidači opasnosti se ne vežu na NLPR3, ali na neki način dovode do njegovog aktiviranja nizvodno. NLRP3 stoga vjerojatno djeluje tako da je opći senzor za stanični stres.

Neodgovarajuća i kronična aktivacija upale povezana je s mnogim bolestima kao što su rak, kardiovaskularne bolesti, dijabetes i autoimune bolesti. S obzirom na više vrsta signala koji mogu aktivirati inflamasom NLRP3, ovaj kompleks je fokus za aktivni razvoj lijekova kako bi se pronašli inhibitori koji bi zaustavili neželjenu upalu. Ovi inflamasomi se nalaze u granulocitima, monocitima (makrofazima), megakariocitima i dendritskim stanicama.

Aktivirani NLRP3 regrutira ASC Adapter Protein, što zatim dovodi do regrutiranja i aktivacije prokapaze 1. NLRP3 ima pirinsku, NACHT i LRR domenu. ASC ima pyrin i CARD domenu. Aktivni LRP3 tada može regrutirati ASC kroz interakcije pyrin:pirin među-proteinske domene. To onda omogućuje CARD domeni vezanog ASC-a da regrutira prokaspazu kroz interakcije CARD:CARD (zapamtite da prokaspaza također ima CARD domenu), tvoreći aktivni NLRP3 inflammasom. Dodatna značajka aktivacije inflamasoma NLRP3 javlja se kada transkripcijski faktor NFkb, koji je aktiviran PAMPovima (signal 1), dovodi do transkripcije i procitokina (IL-1 beta i IL 18) i samog NLRP3.

Stoga su opet potrebna dva signala:

Signal 1

Prvi signali su bakterijski i virusni (virus gripe, poliovirus, enterovirus, rinovirus, humani respiratorni sincicijski virus itd.) PAMP-ovi koji se vežu na TLR i dovode do aktivacije faktora transkripcije NFkb. Time se aktivira ne samo transkripcija pro-interleukina 1-beat i interleukina 18, već i transkripcija samog NLRP3 senzora.

Signal 2

Signal 2 se isporučuje preko PAMP-ova i DAMP-ova neizravno do senzora NLRP3 što dovodi do sklapanja inflamasoma. Čini se da ti DAMP aktiviraju aktivaciju NLRP3 proteina i kasnije stvaranje aktivnog inflamasoma NLRP3. Ali što aktivira NLR3P3? Nakon mnogih studija, postalo je jasno da tipični bakterijski ligandi koji bi aktivirali TLR i možda NLR samo primaju NLRP3 za aktivaciju. Ne vežu se izravno na to.

Izvanstanični ATP je glavni aktivator NLRP3. Poznato je da nanočestice također oslobađaju ATP. Većina studija je pokazala da je K+ efluks iz stanice je rani signal i da se protein NEK7, protein koji fosforilira druge proteine, veže na NLRP3 nakon izljeva iona kalija i aktivira ga. Uklanjanje NEK7 zaustavilo je NLRP3, ali ne i aktivaciju inflamasoma NLRP4. Iako je NLRP3 vezan na NEK7 preko NEK7 katalitičke domene, aktivnost katalitičke domene NEK7 nije bila potrebna.

Što dovodi do K+ izljev? Napravimo sigurnosnu kopiju kako bismo pronašli uzvodne događaje koji bi mogli dovesti do odljeva i pokušajmo pronaći vezu s ATP-om. Pozadina za dio ovog materijala bit će istražena u budućim poglavljima. Događaju se sljedeći koraci kao što je prikazano na slici i informacijama u nastavku:

- krute tvari kao što su silicij, kristali kolesterola, kristali mokraćne kiseline, pa čak i agregirani proteini kao što su prioni mogu biti zahvaćeni monocitima/makrofagom (kao što gutaju bakterije kao dio svoje imunološke funkcije) u procesu koji se zove fagocitoza. Čestice su obavijene dvoslojnom membranom iz plazme koja pupa u stanicu. Ova vezikula se spaja s lizosomom koji se pri tom oštećuje. Zatim otpuštaju ATP u citoplazmu;

- citoplazmatski ATP se tada može kretati izvan stanice kroz kanal glikoproteinske membrane nazvan pannexin 1;

- ekstracelularni ATP se može vezati na drugi membranski protein nazvan purinoceptor P2X7. Ovaj protein sada postaje kationski kanal koji omogućuje K+ efluksa jer ion ima veću koncentraciju unutar stanice nego izvan nje. Izvanstanična ATP "vrata" otvaraju kationski kanal P2X7. Toksin koji stvara pore nigericin iz Streptomyces hygroscopicus također dovodi do izljeva kalijevih iona. Isto tako, proteini koji stvaraju pore iz S. aureus (hemolizini) dovode do efluksa kalijevih iona i aktivacije inflamasoma NLRP3.

Drugi signali također aktiviraju inflamasom NLRP3. To uključuje oštećenje mitohondrija i oslobađanje reaktivnih vrsta kisika.


NLRP3 inflammasom potiče upalu uzrokovanu pretilošću i inzulinsku rezistenciju

Pojava kronične upale tijekom pretilosti u odsutnosti očite infekcije ili dobro definiranih autoimunih procesa zagonetan je fenomen. Obitelj Nod-like receptor (NLR) obitelj senzora urođenih imunoloških stanica, kao što je domena koja veže nukleotide, obitelj bogata leucinom, inflamasom koji sadrži domenu pirina (Nlrp3, ali također poznat kao Nalp3 ili kriopirin) je uključen u prepoznavanju određenih nemikrobnih 'signala opasnosti' koji dovode do aktivacije kaspaze-1 i naknadnog lučenja interleukina-1β (IL-1β) i IL-18. Pokazali smo da je ograničenje kalorija i gubitak težine posredovan vježbanjem u pretilih osoba s dijabetesom tipa 2 povezan sa smanjenjem ekspresije Nlrp3 u masnom tkivu, kao i sa smanjenom upalom i poboljšanom osjetljivošću na inzulin. Nadalje smo otkrili da inflamasom Nlrp3 osjeća povećanje intracelularnog ceramida povezano s lipotoksičnošću kako bi inducirao cijepanje kaspaze-1 u makrofagima i masnom tkivu. Ablacija Nlrp3 kod miševa sprječava aktivaciju inflamasoma uzrokovanu pretilošću u masnim depoima i jetri, kao i pojačava signalizaciju inzulina. Nadalje, eliminacija Nlrp3 u pretilih miševa smanjuje ekspresiju IL-18 i interferona-γ masnog tkiva (IFN-γ), povećava broj naivnih T stanica i smanjuje broj efektorskih T stanica u masnom tkivu. Ovi podaci zajedno utvrđuju da inflamasom Nlrp3 osjeća signale opasnosti povezane s pretilošću i doprinosi upali izazvanoj pretilošću i inzulinskoj rezistenciji.


SAŽETAK

Izvanstanični ATP se veže i signalizira preko P2X7 receptora (P2X7Rs) kako bi modulirao imunološku funkciju kako na način ovisan o upalu tako i na neovisan način. U ovoj studiji, P2X7 -/- miševi, farmakološki agonisti ATP-magnezijeva sol (Mg-ATP 100 mg/kg, EC50 ≈ 1,32 mM) i benzoilbenzoil-ATP (Bz-ATP 10 mg/kg, EC50 ≈ 285 μM), i antagonist oksidirani ATP (oksi-ATP 40 mg/kg, IC50 ≈ 100 μM) korišteni su kako bi se pokazalo da je aktivacija P2X7R ključna za kontrolu mortaliteta, širenja bakterija i upale u vezivanju cekuma i polimikrobne sepse izazvane ubodom kod miševa. Naši rezultati s himernim miševima P2X7 -/- koštane srži, adaptivnim prijenosom peritonealnih makrofaga i P2X7 -/- miševima specifičnim za mijeloide pokazuju da je signalizacija P2X7R na makrofagima ključna za zaštitni učinak P2X7R. P2X7R signalizacija štiti povećanjem ubijanja bakterija od strane makrofaga, što je neovisno o inflamasomu. Korištenjem inhibitora koneksin (Cx) kanala Gap27 (0,1 mg/kg, IC50 ≈ 0,25 μM) i inhibitor paneksinskih kanala probenecid (10 mg/kg, IC50 ≈ 11,7 μM), pokazali smo da je oslobađanje ATP-a kroz Cx važno za inhibiciju upale i bakterijskog opterećenja. Ukratko, ciljanje P2X7R pruža novu priliku za iskorištavanje endogenog zaštitnog imunološkog mehanizma u liječenju sepse.—Csóka, B., Németh, ZH, Törő, G., Idzko, M., Zech, A., Koscsó, B ., Spolarics, Z., Antonioli, L., Cseri, K., Erdélyi, K., Pacher, P., Haskó, G. Izvanstanični ATP štiti od sepse putem purinergičkih receptora P2X7 makrofaga povećavajući unutarstanično ubijanje bakterija. FASEB J. 29, 3626-3637 (2015). www.fasebj.org

Kratice

Sepsa je ozbiljno zdravstveno stanje uzrokovano invazijom mikroba na normalno sterilne dijelove tijela. Procjenjuje se da između 28 i 50% od

700.000 ljudi koji razviju sepsu godišnje umire – daleko više od broja umrlih u SAD-u od raka prostate, raka dojke i AIDS-a zajedno (1-3). Bolesnici sa sepsom su općenito hospitalizirani dulje vrijeme, rijetko napuštajući jedinicu intenzivne njege na 2-3 tjedna (2). Sukladno tome, sepsa predstavlja veliki teret za zdravstveni sustav SAD-a, s troškovima koji se procjenjuju na približno 16,7 milijardi dolara godišnje (4).

Trenutni koncepti sugeriraju da su zatajenje organa i smrtnost u sepsi uzrokovani neprikladnom regulacijom imunološkog sustava (5, 6). Ta se disregulacija očituje kao nemogućnost kontrole rasta i širenja bakterija te prekomjernom upalom, procesima koji su međusobno povezani i uzrokovani, velikim dijelom, disfunkcijom makrofaga. Postoje 2 glavna signalna puta koja pokreću aktivaciju makrofaga u sepsi: jedan je potaknut molekularnim uzorcima povezanim s patogenom (PAMP), drugi molekularnim uzorcima povezanim s opasnostima domaćina (DAMP) (7). Iako su PAMP-ovi bili uobičajeni fokus istraživanja sepse, nedavni dokazi ukazuju na novu ulogu DAMP-a (7). DAMP-ovi sadrže raznoliku skupinu molekula koje se nakupljaju u izvanstaničnom prostoru kao odgovor na uništavanje tkiva posredovano bakterijama, traumu i opekline, a sve su povezane sa sepsom. Primjeri DAMP-a uključuju proteine ​​toplinskog šoka, kutiju 1 grupe visoke pokretljivosti, fragmente hijalurona, mokraćnu kiselinu i ATP.

ATP se oslobađa iz intracelularnog u izvanstanični prostor tijekom upale, infekcije i šoka, što je sve povezano sa sepsom (8, 9). Predloženo je više mehanizama za posredovanje otpuštanja ATP-a tijekom imunološke aktivacije, pri čemu su konneksinski (Cx) hemikanali i panneksinski (Panx) kanali dobili glavni fokus (10, 11). Detekcija oslobođenog ATP-a pomoću purinergičkih receptora P2 na upalnim stanicama upozorava imunološki sustav na opasnost te pokreće i orkestrira imunitet i upalu domaćina. P2 receptori spadaju u 2 klase: ionotropni P2X receptori (P2X1-7R) i P2YR spojeni na G protein (P2Y1,-2,-4,-6,-11,-12,-13 i -14) (9 ).

P2X7R su glavni imunoregulacijski P2R i eksprimirani su na najvišim razinama na stanicama imunološkog sustava (12). Makrofagi imaju 4 do 5 puta veću ekspresiju P2X7RS nego B, T i NK stanice (12). Ekspresija P2X7R na neutrofilima je kontroverzna. Neke studije su pokazale da je prisutan intracelularno, ali ne i na površini stanice (12, 13), dok je jedna studija pokazala da ima antiapoptotske učinke na neutrofile (14). Aktivacija makrofaga povezana je s povećanom ekspresijom P2X7R (15).

Jedan od najbolje okarakteriziranih aspekata funkcije P2X7R je njegova sposobnost da aktivira inflamasomski sklop P3 (NLRP3) domene koja veže nukleotide bogate leucinom koji sadrži ponavljanje u makrofagima, čime pokreće IL-1β posredovan kaspazom-1 i - 18 obrada i puštanje (16, 17). Osim toga, višestruki dokazi dokumentiraju pojavu uloge P2X7R u povećanju prepoznavanja, fagocitoze i ubijanja patogena od strane makrofaga (18-20). Nedavne studije su predložile da ATP kontrolira patogene putem piroptoze ovisne o inflamasomima (21). Prema ovom konceptu, ATP uzrokuje aktivaciju kaspaze-1, što zatim dovodi do piroptotičke smrti makrofaga, koju karakterizira brz gubitak integriteta stanične membrane i oslobađanje citosolnog sadržaja, uključujući bakterije. Otpuštene bakterije tada mogu biti progutane i ubijene od strane regrutiranih neutrofila na način koji je neovisan o IL-1β i -18 (22).

Unatoč rastućim dokazima koji podupiru važnu ulogu ATP-a i P2X7R u reguliranju upale i bakterijske fagocitoze i eliminacije makrofaga in vitro, uloga ATP-a i P2X7R u reguliranju odgovora domaćina na sepsu nije jasna. U ovoj studiji testirali smo hipotezu da endogeno otpušten ATP kontrolira upalni odgovor domaćina na sepsu putem P2X7 signalizacije na makrofagima.


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RESIDENT FIBROBLASTS AND OTHER CELLS

In many tissues, including skin, heart, and lung, the presence of poorly defined resident fibroblasts has been well described, and these cells have been relatively easy to culture and study in vitro. However, until very recently the precise nature of resident fibroblasts [cells embedded in connective tissue (stroma) that produce collagen and other fibers] was poorly understood (70, 74). EM studies have revealed that many of these cells have close relationships with epithelial or endothelial cells. In lung development, the critical role of stromal cells in epithelial differentiation has been well described. Recent studies that have enabled easy visualization of these cells indicate that they are much more extensively distributed than previously thought and that they may have critical functions in homeostasis, including pericyte functions. Many resident fibroblasts also have close associations with epithelial cells and may function as epithelial pericytes.

Surrounding the arterioles are perivascular fibroblasts or fibrocytes (21, 70, 74). These cells may be termed adventitial cells in other texts, and evidence suggests they have important immunomodulatory functions and that some serve as vessel wall progenitors (80). In some tissues, including skin and liver, some resident adult microvascular wall mesenchymal cells (i.e., pericytes) have progenitor cell functions (81) that is, they can differentiate into mature cells of the tissue, including vascular smooth muscle, white adipocytes, and possibly neurons. It is unclear whether all adult mesenchyme cells have this ability to act as progenitors for other cell types within their organ, or whether there are more restricted subpopulations of perivascular cells that have this capacity.

Studies over the past several years have investigated some of the signaling pathways involved in pericyte-to-myofibroblast transition. Although this area is rapidly evolving, it appears that the same signaling pathways that regulate angiogenesis in cross talk between endothelial cells and pericytes are critical in pericyte and fibroblast activation. Those pathways include TGF-β, PDGFR-β, PDGFR-α, and VEGF receptor 2 (VEGFR2). Indeed, loss-of-function studies of these pathways have shown them to be critical in the early events of pericyte activation, the appearance of myofibroblasts, and fibrogenesis. Other developmental pathways that are important in building the vasculature may also be significant in the development of a myofibroblast. These pathways include angiopoietin signaling sphingosine kinase signaling and the developmental pathways WNT, Hedgehog, and Notch. Current evidence suggests that in development these signaling pathways are carefully regulated but that in disease they are markedly dysregulated, resulting in an overactivated phenotype relative to development. It may be desirable to 𠇍ial down” these over-activated developmental signaling pathways to counteract the appearance of myofibroblasts in tissues. Also, extracellular regulators of the VEGFR signaling pathway and metalloproteinases play important roles in the activation of pericyte function. Pericytes must detach from capillaries, spread, and migrate and must withdraw from the CBM, which requires proteolytic activity. One such factor that is activated strongly and early after injury in kidney pericytes is the metalloproteinase ADAMTS1 (87). In different organs, distinct metalloproteinases probably play important roles in pericyte acquisition of the myofibroblast phenotype, and these metalloproteinases may prove to be useful targets in reversal of phenotype.


Nonstandard Abbreviations and Acronyms

AnakInRa for Treatment of Recurrent Idiopathic Pericarditis

acute myocardial infarction

apoptosis-associated spec-like protein containing a carboxy-terminal containing a caspase recruiting domain

Canakinumab Anti-inflammatory Thrombosis Outcomes Study

Cardiovascular Inflammation Reduction Trial

Colchicine Cardiovascular Outcome Trial

damage-associated molecular patterns

Diastolic Heart Failure Anakinra Response Trial(s)

low-density lipoprotein receptor

Medical Royal Council Heart studyInterLeukin-1 Antagonist Heart Study

myeloid differentiation factor 88

NACHT LRR and PYD domains-containing protein 3

N-terminal pro-B-type natriuretic peptide

Recently Decompensated Heart Failure Anakinra Response Trial(s)

suppressor of tumorigenicity 2

ST-segment–elevation myocardial infarction

Virginia Commonwealth University Anakinra Remodeling/Response Trial(s)

Sources of Funding and Disclosures

A. Abbate has received research grant funding and has served as a paid scientific advisor to GSK, Kiniksa, Merck, Novartis, Olatec, Serpin Pharma, and Swedish Orphan Biovitrum S. Toldo has received research grant funding from Kiniksa, Olatec and Serpin Pharma. C. Marchetti serves as Director for Olatec’s Innovative Science Program and has equity in Olatec B.W. Van Tassell has received research grant funding from Swedish Orphan Biovitrum, and he has served as a paid scientific advisor to Serpin Pharma C.A. Dinarello serves as Chairman of Olatec’s Scientific Advisory Board, is co-Chief Scientific Officer, receives compensation and has equity in Olatec. The other author reports no conflicts.

Fusnote

For Sources of Funding and Disclosures, see page 1275.


Rasprava

Our BioID screen identified Spata2 as a CYLD-interacting protein, and the Spata2-CYLD interaction was also discovered by other groups using different strategies (Elliott et al, 2016 Kupka et al, 2016 Schlicher et al, 2016 Wagner et al, 2016 ). The best known function of Spata2 is to act as a CYLD partner protein that recruits CYLD to TNFSC complex for deubiquitination of RIP1 and initiation of necroptosis (Elliott et al, 2016 Kupka et al, 2016 Wagner et al, 2016 Wei et al, 2017 ). The results presented in this paper established Spata2 as a novel regulator of NLRP3 inflammasome activation and inflammatory responses. Our data suggest that Spata2 is located in and recruits its partner CYLD to the centrosome, which is in agreement with a recent work documenting the association of endogenous Spata2 and CYLD with well-known centrosomal proteins (Gupta et al, 2015 ). Spata2 and CYLD physically interact with the centrosomal kinase PLK4 to deconjugate K63-linked polyubiquitin chains from PLK4, thereby facilitating the physical interaction of PLK4 with NEK7. Based on these data, we propose a new model that PLK4 inhibits NLRP3 inflammasome activation through its direct phosphorylation of NEK7, which in turn inhibits the NEK7-NLRP3 interaction (Fig 7E). Our data demonstrate a dynamic interplay between the centrosome and inflammasome and provide valuable insight into the molecular mechanism of the NEK7-mediated NLRP3 inflammasome activation.

A number of E3 ligases have been discovered to regulate NLRP3 inflammasome by conjugating ubiquitin chains onto NLRP3, ASC, caspase-1, or upstream regulators (Lopez-Castejon & Edelmann, 2016 ). The E3-mediated ubiquitination of NLRP3 inflammasome can be reversed by DUBs, but less is known about the DUBs that are involved in this process. Previously, BRCC3 was shown as a major DUB to promote inflammasome activation by directly removing ubiquitination of NLRP3 (Py et al, 2013 Ren et al, 2019 ). Another DUB capable of regulating inflammasome activation is A20. In contrast to BRCC3, A20 inhibits NLRP3 inflammasome activation by restricting ubiquitination of pro-IL-1β protein complexes (Vande Walle et al, 2014 Duong et al, 2015 ). Our study identified CYLD as a DUB that negatively regulates NLRP3 inflammasome activation by catalyzing the deubiquitination of an upstream regulator PLK4, instead of the inflammasome components themselves.

The centrosome is a non-membrane-bound organelle composed of a pair of centrioles surrounded by a large set of proteins termed pericentriolar material (PCM). The classic function of the centrosome is to serve as a major microtubule-organizing center (MTOC) regulating cell cycle progression in animal cells. In addition, it has been shown that the centrosome is involved in immunological synapse formation between T cells and antigen-presenting cells (Vertii et al, 2016a ). Apart from the role in regulating adaptive immunity, a recent study indicates that the centrosome mediates the secretion of cytokines in response to proinflammatory stimuli which induce atypical interphase centrosome maturation in a manner independent of classic mitotic kinase PLK1(Vertii et al, 2016b ). This links the interphase centrosome to innate immune response. Interestingly, upon NLRP3 activation, cells in interphase of cell cycle are capable of producing much higher levels of active caspase-1 and IL-1β than those produced by mitotic cells (Shi et al, 2016 ), suggesting that interphase is the major phase for NLRP3 inflammasome activation. Surprisingly, a more recent paper demonstrates that NLRP3 is positioned to and assembles with ASC in the centrosome upon inflammasome activation, and abnormal positioning of NLRP3 would compromise the inflammasome activity (Li et al, 2017 ). In agreement with this finding, our immunofluorescence results indicated that upon activation a substantial number of NLRP3 inflammasomes, represented by ASC specks, are associated with centrosomes during early stage of activation (Appendix Fig S13). Together, these findings reveal a cross-talk between the centrosome and NLRP3 inflammasome. Additionally, our discovery that Spata2, CYLD, and PLK4 function in the same signaling axis in the centrosome to regulate inflammasome activation suggests a critical role for centrosomal proteins in controlling the activation of NLRP3 inflammasome.

PLK4 is a well-known cell cycle regulator that controls centrosome duplication and some aspects of mitosis (Maniswami et al, 2018 ). In this study, we found a previously unknown function for PLK4. PLK4 suppressed NLRP3 inflammasome activation by specifically phosphorylating NEK7 during LPS-mediated priming step, which in turn inhibited the interaction of NEK7 with NLRP3 and inflammasome activation. This study also defines the phosphorylation status of NEK7 as a previously uncharacterized factor fine-tuning NLRP3 inflammasome activation. Recently, a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7 was solved to understand the mechanism of NEK7-NLRP3 interaction (Sharif et al, 2019 ). This structure demonstrated that the NEK7 C-lobe interacts with NLRP3 and the two halves of the NEK7 C-lobe (AA120–259 and 260–302) form the two interfaces of NEK7-NLRP3 interaction. While Ser204 is located in the first half of the NEK7 C-lobe, it is not among the residues that directly interact with NLRP3. Therefore, it is reasonable to deduce that NEK7 Ser204 phosphorylation may inhibit NEK7-NLRP3 interaction indirectly rather than directly, e.g., by favoring NEK7 binding to other proteins. In support of this notion, we found that Ser204 phosphorylation is also involved in a non-NLRP3 inflammasome regulating function of NEK7 (Tan et al, 2017 ). The TRF1 stabilizing function of NEK7 was largely controlled by Ser204 phosphorylation (Tan et al, 2017 Appendix Fig S14).

How PLK4 and NEK7 are switched from cell cycle regulators to inflammasome regulators during inflammasome activation remains elusive. One possibility is that LPS priming alters the structure of the centrosome and changes the function of the proteins residing inside, including PLK4 and NEK7. It is reported that 4–6 h of LPS stimulation led to recruitment of more centrosome proteins to PCM and marked increase in the size of interphase centrosomes, resulting in enhanced microtubule nucleation, enriched recycling endosomes, and more secretion of cytokines (Vertii et al, 2016b ). These data suggest that hours of LPS stimulation may drastically change the state of interphase centrosomes. Consistent with this notion, in a screen for new signaling components for TLR response in dendritic cells, PLK4 was found to be involved in LPS-induced antiviral response in a cell cycle-independent manner (Chevrier et al, 2011 ). In this case, PLK4 transcript was markedly enhanced after a few hours of LPS stimulation with concomitant NEK7 phosphorylation increase although the phosphorylation site(s) was not identified (Chevrier et al, 2011 ). This phosphorylation induction was suppressed with a pan PLK inhibitor (Chevrier et al, 2011 ), which is consistent with our finding that PLK4 phosphorylated NEK7 at S204 at the time point of 4 h of LPS priming. While the physiological significance of PLK4 in regulating inflammasome activation remains unclear, we speculate that LPS-stimulated PLK4 expression/activation and subsequent NEK7 phosphorylation might serve as a break in the location where NLRP3 inflammasome is assembled and activated to tightly restraint inflammasome activity to a proper level so as to avoid deleterious effect of excessive activation.

As a key regulator of centrosome duplication, an appropriate level of PLK4 is critical for keeping the right number of centrosomes during cell divisions which would otherwise produce chromosomal instability and aneuploidy (Maniswami et al, 2018 ). Deregulated expression of PLK4 has been associated with multiple cancers, and PLK4 has become a drug target for cancer treatment (Maniswami et al, 2018 ). In this regard, its target NEK7 has recently been shown to control the integrity of telomere shelterin protein complex (Tan et al, 2017 ). It would be worthwhile to investigate whether aberrant activation of NLRP3 inflammasome contributes to tumorigenesis in cancers associated with deregulation of PLK4 and NEK7.

In summary, our findings define a centrosomal Spata2/CYLD-PLK4 signaling axis that suppresses NLRP3 inflammasome activation by a PLK4-mediated NEK7 phosphorylation, which in turn attenuates the association of NEK7 with NLRP3 leading to the inhibition of abnormally high inflammasome activation. Our data shed new light on the understanding of the centrosome as a platform for inflammasome assembly and activation and provide novel potential therapeutic targets for treatment of NLRP3 inflammasome-mediated inflammatory diseases.


F5. Recognition and Response in the Innate Immune System

  • Contributed by Henry Jakubowski
  • Professor (Chemistry) at College of St. Benedict/St. John's University

The adaptive immune response must be activated by cells of the innate immune system. These cells must recognized viruses and living cells like bacteria, fungi, and protozoans like amoebas. There are often common structural features in these different classes of cells. The cells of the innate system (dendritic cells, macrophages, eosinophils, etc) have receptors (Toll-like Receptors 1-10 or TLRs) that recognize the common pathogen associated molecular patterns (PAMPs) , which leads to binding, engulfment, signal transduction, maturation (differentiation), antigen presentation, and cytokine/chemokine release from these cells. Take for example dendritic cells, which reside in the peripheral tissues and act as sentinels. They can bind PAMPs which include:

  • CHO/Lipids on bacteria surface (LPS)
  • mannose (CHO found in abundance on bacteria,
  • yeast dsRNA (from viruses)
  • nonmethylated CpG motiffs in bacterial DNA

Bacterial and viral nucleic acids are recognized by intracellular TLRs in the cell after the they been taken up into the cells by endocytosis. Dendritic cells phagocytize microbial and host cells killed through programmed cell death (apoptosis). In the process of maturation, surface protein expression is altered, allowing the cells to leave the peripheral tissue and migrate to the lymph nodes where they activate T cells through the antigen presentation methods described above. They also control lymphocyte movement through release of chemokines. The very large figure below shows the processes involved in recognition of PAMPs by TLRs of innate immune system cells.


Role of Interleukins on Physiological and Pathological Bone Resorption and Bone Formation: Effects by Cytokines in The IL-1 and IL-2 Families

Interleukin-37

High levels of IL-37 protein and increased numbers of IL-37 expressing cells have been detected in clinical specimens from patients with infected bone lesions ( Tang et al., 2018 ). The authors also report that local osteoclast formation and bone loss caused by injection of LPS s.c. on the top of skull bones in mice is abolished by treatment with human IL-37. Systemic loss of trabecular bone in distal femur caused by LPS-treatment was also inhibited by IL-37. This may be explained by the well-known anti-inflammatory effect of IL-37, but effects on osteoclastogenesis may also contribute. The latter possibility is suggested by the fact that RAW264.7 cell line and human macrophages express IL-37 receptors, which when activated results in decreased expression of cytokines such as IL-1β, TNF-α and IL-6 ( Li et al., 2015 Schauer et al., 2017 ). It was also found that IL-37 could inhibit RANKL-stimulated osteoclast formation using both RAW264.7 cells and mouse bone marrow macrophages as osteoclast progenitor cells ( Tang et al., 2018 ). This effect was associated with MyD88-dependent decreased expression of osteoclastic and osteoclastogenic genes in the osteoclast progenitor cells. It was also found that IL-37 could inhibit osteoclastogenesis in RANKL-primed, LPS-stimulated bone marrow macrophages. In contrast, Saeed et al. report that, although IL-37 inhibited LPS-induced osteoclast formation in vivo, IL-37 did not inhibit RANKL- or LPS-induced osteoclast formation in mouse bone marrow macrophage cultures ( Saeed et al., 2016 ). The effect by IL-37 on osteoclast numbers in vivo was associated with decreased expression of RANKL, IL-1β and TNF-α. However, IL-37 did not affect LPS-induced RANKL expression in stromal cells and the authors therefore conclude that IL-37 inhibits osteoclast formation and RANKL expression in vivo indirectly by decreasing the expression of IL-1β and TNF-α. It seems IL-37 can inhibit osteoclast formation by both indirect and direct mechanisms.

It is not known if IL-37 may affect bone formation, but it has recently been shown that IL-37 can inhibit alkaline phosphatase activity and mineralization in aortic valve interstitial cell cultures, an effect associated with decreased levels of BMP-2 ( Zeng et al., 2017 ). The thickening of aortic valve seen in mice exposed to a TLR4 agonist, or high fat diet, was decreased in mice expressing human Il37.


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Keywords: monocytes, Warburg effect, fatty acid oxidation, glucose deprivation, inflammation

Citation: Raulien N, Friedrich K, Strobel S, Rubner S, Baumann S, von Bergen M, Körner A, Krueger M, Rossol M and Wagner U (2017) Fatty Acid Oxidation Compensates for Lipopolysaccharide-Induced Warburg Effect in Glucose-Deprived Monocytes. Ispred. Immunol. 8:609. doi: 10.3389/fimmu.2017.00609

Received: 10 March 2017 Accepted: 09 May 2017
Published: 29 May 2017

Kiichi Hirota, Kansai Medical University, Japan
Nicola Tamassia, University of Verona, Italy

Copyright: © 2017 Raulien, Friedrich, Strobel, Rubner, Baumann, von Bergen, Körner, Krueger, Rossol and Wagner. Ovo je članak otvorenog pristupa koji se distribuira pod uvjetima licence Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Nije dopuštena nikakva uporaba, distribucija ili reprodukcija koja nije u skladu s ovim uvjetima.


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Komentari:

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    What suitable words ... phenomenal, magnificent thinking

  7. Gokree

    Mislim da nisi u pravu. Siguran sam. Pozivam vas na raspravu. Pišite u PM, javit ćemo se.



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