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Abstract
SUMMARYInterleukin-1 (IL-1) is a key regulator of inflammation and ischaemic brain injury, but the contribution of central and peripheral sources of IL-1 to brain injury is not well understood. Here we show that haematopoietic-derived IL-1 is a key driver of ischaemic brain injury. Wild type (WT) mice transplanted with IL-1αβ-deficient bone marrow displayed a significant (40%) reduction in brain injury induced by focal cerebral ischaemia compared with WT mice transplanted with WT bone marrow. This was paralleled by improved neurological outcome and the almost complete absence of splenic-derived, but not liver-derived, IL-1α after stroke in WT mice lacking haematopoietic-derived IL-1. IL-1αβ knockout (KO) mice transplanted with IL-1αβ-deficient bone marrow showed a 60% reduction in brain injury compared with WT mice receiving WT bone marrow. Transplantation of WT bone marrow in IL-1αβ KO mice resulted in a similar level of blood-brain-barrier injury to that observed in WT mice receiving IL-1αβ-deficient bone marrow. Cerebral oedema after brain injury was reduced in IL-1αβ KO recipients irrespective of donor-derived IL-1, but a lack of haematopoetic IL-1 has also been associated with smaller brain oedema independently of recipient status. Thus, both central and haematopoietic-derived IL-1 are important contributors to brain injury after cerebral ischaemia. Identification of the cellular sources of IL-1 in the periphery could allow targeted interventions at these sites.
Highlights
Neuroinflammatory changes in cerebral ischaemia and other central nervous system (CNS) diseases are driven by both activated glia and peripheral immune cells (Ransohoff and Brown, 2012; Denes et al, 2010a)
Central and haematopoietic-derived IL-1 both contribute to ischaemic brain injury Bone marrow transplantation (Fig. 1A) was successful, as shown by the fact that blood chimerism was 88-91% in wild-type (WT) and IL-1αβ knockout (KO) recipients based on flow cytometric data (Fig. 1B) and no difference in total leukocyte numbers or relative proportion of different leukocyte subsets was found among groups prior to middle cerebral artery occlusion (MCAo)
WT mice transplanted with IL-1αβ KO bone marrow (KO to WT) displayed a 40% reduction in infarct size compared with the injury seen in WT mice receiving WT bone marrow (WT to WT), whereas IL-1αβ KO mice transplanted with WT bone marrow (WT to KO) showed a 50% reduction compared with the WT to WT (Fig. 1C,D)
Summary
Neuroinflammatory changes in cerebral ischaemia and other central nervous system (CNS) diseases are driven by both activated glia and peripheral immune cells (Ransohoff and Brown, 2012; Denes et al, 2010a). Interleukin-1 (IL-1), a master cytokine and key inflammatory mediator, is a major contributor to ischaemic brain injury (Denes et al, 2011a; Dinarello, 2011). IL-1 of both central and peripheral origin is likely to influence CNS disease, but the cellular sources and relative contribution of endogenous peripheral versus central IL-1 to brain injury are still unclear. Experimental brain injury, microglia are considered to be the main source of central IL-1, of which IL-1β is the best studied (Davies et al, 1999; Hanisch, 2002). IL-1 protein levels in microglia are very low in the first 4 hours after cerebral ischaemia in mice, and the main early isoform expressed in the brain is IL1α (Luheshi et al, 2011).
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