Mononuclear myeloid cells mount an adaptive protective response to intracerebral haemorrhage by activation of NRF2
Loan, J.; Qiu, J.; Barrington, J.; Baxter, P. S.; McKay, S.; He, X.; Kirby, C.; McDade, K.; Beniazza, M.; McQueen, J.; Schaper, F.; Cheng, Y.; Geary, B.; Dando, O. R.; Smith, C.; Samarasekera, N.; Salman, R. A.-S.; McColl, B. W.; Hardingham, G. E.
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Following intracerebral haemorrhage (ICH), secondary injury contributes to negative outcomes. Here, we describe inter-dependent injurious and adaptive-protective pathways that form a therapeutically modifiable ICH response. In perihaematomal tissue from post-mortem ICH patients, transcriptomic analysis pointed to concurrent perihaematomal activation of the cytoprotective stress-induced transcription factor NRF2 and activation of interferon responses, with mononuclear myeloid cells (microglia and monocyte-derived cells, MMCs) and astrocytes contributing to this signature. In vitro, microglia-astrocyte-neuron co-culture studies revealed that microglial NRF2 activation was induced by clot-conditioned medium and could influence the interferon pathway in both microglia themselves as well as astrocytes. In vivo, MMC-specific deletion of NRF2 inhibited NRF2 target-gene induction, exacerbated interferon pathway activation following ICH, and impaired functional recovery. Pharmacological NRF2 activation suppressed interferon pathway induction post-ICH, and direct interferon pathway antagonism rescued neurological recovery deficits caused by MMC-specific NRF2 deficiency. Thus, augmenting NRF2- or inhibiting interferon-signalling may improve outcomes after ICH.
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