Ablation of type-1 IFN signalling in hematopoietic cells confers protection following traumatic brain injury

Abstract

Type-1 interferons (IFNs) are pleiotropic cytokines, that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the central nervous system. In this study, we have investigated the role of type-1 IFNs in neuro-inflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8-10 week-old male C57BL/6J WT and IFNAR1^-/- mice and brains were excised to study infarct volume, inflammatory mediator release via qPCR analysis and immune cell profile via immunohistochemistry. IFNAR1^-/- mice displayed smaller infarcts compared to WT mice after TBI. IFNAR1^-/- mice exhibited an altered anti-inflammatory environment compared to WT mice, with significantly reduced levels of the pro-inflammatory mediators TNFα, IL-1β and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1h before, 30 min after or 30min and 2d after TBI displayed significantly improved histological and behavioural outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuro-inflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human post-mortem TBI brains. Taken together, these data demonstrate that type-1 IFN signalling is a critical pathway in the progression of neuro-inflammation and presents a viable therapeutic target for the treatment of TBI.

Significance Statement: This research article investigates the inflammatory effect of type-1 interferons (IFN) in traumatic brain injury (TBI), in both human and mice. IFNs have been traditionally associated with peripheral inflammatory responses. However, these molecules are also present in the central nervous system and we believe that they play a key role in the control of neuroinflammation. Our study shows that reducing type-1 IFN signalling, either by genetic ablation or by pharmacological intervention, has a beneficial effect on the outcome after TBI. IFN signalling is required for the brain to mount an inflammatory response to the insult of TBI. This study addresses key issues in type-1 IFN signalling and is a seminal discovery of their role in TBI.