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Marinelli, Carla (2015) Toll-like receptors as transducer of inflammatory signals in glia:
the astrocyte-microglia connection.
[Tesi di dottorato]

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Abstract (inglese)

In physiological conditions glia in the central nervous system (CNS) can produce and release protective factors such as anti-oxidant molecules and neurotrophic factors (Sofroniew et al., 2010). Events that impinge on CNS homeostatic balance can induce local inflammatory responses (Carson et al., 2006). Reactive glia can participate producing pro-inflammatory mediators such as chemokines, cytokines, purines and free radicals.
Toll-like receptors (TLRs) are involved in injury responses of nervous system tissue and in neuropathic pain. Here we have investigated the cross-talk mechanisms between glial cells in the CNS making use of an in vitro cellular model, evaluating how glia respond to TLR agonists based on cytokine synthesis and release as well as TLR mRNA/protein expression as readouts.
In order to analyze specific molecular parameters involved in the genesis and maintenance of inflammation, purified microglia and astrocyte-enriched cultures were generated from cerebral cortex of 1-2 day-old rat pups. For some experiments the enriched astrocyte cultures were purified by treatment with L-leucyl-L- leucine methyl ester (L-LME), which selectively depletes cultures of microglia. Activation of microglia and astrocytes (± L-LME) was achieved by treatment with lipopolysaccharide (LPS, TLR4 agonist); zymosan (TLR2 agonist) and poly(I:C) (TLR3 agonist) for 6 and 24 hours.
Gene expression analysis (Real Time-polymerase chain reaction) revealed the ability of microglia to induce mRNA coding for interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In contrast, purified (nominally microglia-free) astrocyte cultures were not responsive to TLR agonists – unlike their astrocyte-enriched counterpart. Mediator production and release into the culture medium (analysed by ELISA) confirmed that microglia themselves respond to pathogenic stimuli. Utilizing flow-cytometric analysis we evaluated the expression of TLR receptors on the cell surface (TLR2/4) or in endosomal membranes (TLR3) after 1, 6 or 24 hours of stimulation with TLR agonists.
Non-neuronal cell responsiveness to pathogenic stimuli is almost always linked to the production of inflammatory mediators. In this context we asked if the apparent inability of purified astrocytes to express a pro-inflammatory phenotype was dependent on the absence of the relevant TLR. Using confocal microscopy, stimulation with LPS conjugated with a fluorochrome showed the presence of TLR4 on the astrocyte cell surface. and Western blot analysis revealed the presence of the co-receptors MD2 and CD14. As consequence, purified astrocytes have been studied in flow cytometry to evaluate alteration in TLR protein expression.
Moreover, we reconstituted the inflammatory profile in astrocyte cell cultures by adding fixed numbers of purified microglia (10% of contaminating cells final). Although the latter 'co-cultures' express pro-inflammatory cytokines after TLR agonist stimulation the absolute levels are inferior to those measured in enriched astrocytes (<5% of contaminating microglia.
To further address the issue of whether microglial cell activation in the presence of astrocytes results from either physical interaction between cell membranes or chemical induction mediated by the release of mediator(s) into the culture medium, a “Transwell insert” system was used. The astrocyte/microglia co-culture paradigm described here may provide a useful starting point to elucidate the molecular mechanisms underlying astrocyte- and microglia-specific responses pertaining to, although not limited to, CNS inflammation, especially where TLR activation plays a role.

Abstract (italiano)

Nel sistema nervoso centrale (SNC), le cellule gliali in condizioni fisiologiche producono e rilasciano sostanze protettive come molecole anti-ossidanti e fattori neurotrofici (Sofroniew et al., 2010). Tutti gli eventi che alterano l’equilibrio omeostatico inducono una risposta infiammatoria locale (Carson et al., 2006). La glia reattiva partecipa producendo mediatori dell’infiammazione come chemochine, citochine, purine e radicali liberi.
I recettori Toll-like (TLRs) sono coinvolti nelle risposte da danno indotto a carico del tessuto nervoso e nel dolore neuropatico.
Nel nostro studio abbiamo investigato i meccanismi di comunicazione tra le cellule della glia attraverso la realizzazione di un modello cellulare in vitro idoneo alla valutazione della risposta gliale al trattamento con agonisti dei TLRs, valutando sia l’espressione di molecole associate all’attivazione dei recettori sia la modulazione genica/proteica degli stessi TLRs.
Per poter valutare meglio la genesi e la progressione dello stato infiammatorio, colture di microglia purificata e colture arricchite in astrociti (≥95%) sono state ottenute dal sacrificio di ratti neonati di 2 giorni e dalla successiva dissezione corticale. Per i nostri esperimenti le colture arricchite di astrociti sono state trattate con L-leucil-L-Leucina estere metilico (L-LME) al fine di ottenere una coltura purificata di astrociti (≥99%).
L’attivazione della microglia e degli astrociti (± L-LME) è stata indotta dal trattamento con lipopolisaccaride (LPS, agonista del TLR4), zymosan (agonista del TLR2) e poli(I:C) (agonista del TLR3) per 6 e 24 ore.
L’analisi dell’espressione genica (in Real Time PCR) ha permesso di dimostrare la capacità delle cellule della glia di indurre la trascrizione di mRNA codificante per interleuchina-1β (IL-1β), interleuchina-6 (IL-6) e tumor necrosis factor-α (TNF-α). La coltura purificata di astrociti non risponde al trattamento con agonisti TLRs, diversamente dalla coltura arricchita in astrociti in cui persiste una piccola percentuale di cellule della microglia.
La produzione e il rilascio nel terreno di coltura di mediatori dell’infiammazione (dosaggio ELISA) confermano che la microglia risponde allo stimolo patogenico. Inoltre le analisi di citofluorimetria hanno permesso di valutare l’espressione dei TLRs sulla membrana cellulare (TLR2/4) e sulla membrana degli endosomi (TLR3) dopo 1 ora, 6 ore e 24 ore di trattamento.
La responsività delle cellule non-neuronali ad uno stimolo lesivo viene solitamente valutata sulla base della capacità delle cellule di produrre mediatori pro-infiammatori. Alla luce di queste evidenze abbiamo voluto chiarire se l’apparente assenza di responsività della coltura purificata di astrociti, dipendesse da alterazioni a carico della struttura recettoriale. Utilizzando la microscopia confocale, abbiamo marcato le cellule con LPS coniugato con un fluorocromo dimostrando la presenza del TLR4 sulla superficie cellulare degli astrociti e le analisi di Western Blot hanno permesso di confermare anche la presenza dei co-recettori CD14 e MD2.
In particolare, lo studio sugli astrociti purificati è stato approfondito mediante citofluorimetria per valutare le alterazioni a carico dell’espressione proteica dei TLRs.
Un’ulteriore batteria di esperimenti è stata condotta ripristinando il profilo infiammatorio aggiungendo un numero fisso di cellule di microglia (per un totale del 10% di cellule contaminanti) ad una coltura purificata di astrociti.
Sebbene la ri-aggiunta di microglia su un monostrato di astrociti purificati (≥99%) ripristini il profilo infiammatorio della coltura, in termini di valore assoluto la quantità di citochine prodotte e rilasciate è comunque inferiore ai valori misurati nella coltura arricchita in astrociti (in cui la contaminante microgliale è ≤5%). Per meglio chiarire se l’attivazione microgliale in presenza di astrociti dipendesse da il contatto fisico tra le membrane cellulari oppure da fattori chimici abbiamo allestito un sistema “Transwell”.
Il paradigma descritto della co-coltura astrociti/microglia protrebbe rappresentare un utile punto di partenza per chiarire i meccanismi molecolari che sottendono le specifiche risposte delle singole popolazioni cellulari all’infiammazione, non solo del SNC, specialmente in tutti quei meccanismi che prevedono il coinvolgimento dei recettori TLRs.

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Tipo di EPrint:Tesi di dottorato
Relatore:Zusso, Morena
Correlatore:Skaper, Stephen
Dottorato (corsi e scuole):Ciclo 27 > scuole 27 > SCIENZE FARMACOLOGICHE > FARMACOLOGIA MOLECOLARE E CELLULARE
Data di deposito della tesi:20 Gennaio 2015
Anno di Pubblicazione:20 Gennaio 2015
Parole chiave (italiano / inglese):Toll-like receptor, Glia, Neuroinflammation
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:7500
Depositato il:01 Dic 2015 16:17
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