Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke

Bettina Hjelm Clausen, Kate Lykke Lambertsen, Frederik Dagnæs-Hansen, Alicia Babcock, Christian Ulrich von Linstow, Michael Meldgaard, Bjarne Winther Kristensen, Tomas Deierborg, Bente Finsen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Cell-based therapies are emerging as new promising treatments in stroke. However, their functional mechanism and therapeutic potential during early infarct maturation has so far received little attention. Here, we asked if cell-based delivery of the interleukin-1 receptor antagonist (IL-1Ra), a known neuroprotectant in stroke, can promote neuroprotection, by modulating the detrimental inflammatory response in the tissue at risk. We show by the use of IL-1Ra-overexpressing and IL-1Ra-deficient mice that IL-1Ra is neuroprotective in stroke. Characterization of the cellular and spatiotemporal production of IL-1Ra and IL-1α/β identifies microglia, not infiltrating leukocytes, as the major sources of IL-1Ra after experimental stroke, and shows IL-1Ra and IL-1β to be produced by segregated subsets of microglia with a small proportion of these cells co-expressing IL-1α. Reconstitution of whole body irradiated mice with IL-1Ra-producing bone marrow cells is associated with neuroprotection and recruitment of IL-1Ra-producing leukocytes after stroke. Neuroprotection is also achieved by therapeutic injection of IL-1Ra-producing bone marrow cells 30 min after stroke onset, additionally improving the functional outcome in two different stroke models. The IL-1Ra-producing bone marrow cells increase the number of IL-1Ra-producing microglia, reduce the availability of IL-1β, and modulate mitogen-activated protein kinase (MAPK) signaling in the ischemic cortex. The importance of these results is underlined by demonstration of IL-1Ra-producing cells in the human cortex early after ischemic stroke. Taken together, our results attribute distinct neuroprotective or neurotoxic functions to segregated subsets of microglia and suggest that treatment strategies increasing the production of IL-1Ra by infiltrating leukocytes or microglia may also be neuroprotective if applied early after stroke onset in patients.

Original languageEnglish
JournalActa Neuropathologica
Volume131
Issue number5
Pages (from-to)775-791
ISSN0001-6322
DOIs
Publication statusPublished - 9. Feb 2016

Keywords

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Focal cerebral ischemia
  • Human brain
  • IL-1α/β
  • Inflammation
  • Macrophages
  • Microglia

Fingerprint Dive into the research topics of 'Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke'. Together they form a unique fingerprint.

Cite this