Mononuclear myeloid cells mount an adaptive protective response to intracerebral haemorrhage by activation of NRF2

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.