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

Clausen BH, Lambertsen KL, Dagnæs-Hansen F, Babcock AA, von Linstow CU, Meldgaard M, Kristensen BW, Deierborg T, Finsen B - Acta Neuropathol. (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winsloewsvej 25, 5000, Odense C, Denmark. bclausen@health.sdu.dk.

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.

No MeSH data available.


Related in: MedlinePlus

IL-1Ra production in the human stroke brain. a–d IHC showing IL-1Ra+ cells in the peri-infarct (a) and infarct core (b), 24 h after stroke onset. c, d IHC staining of parallel sections showing the IgG2a isotype control (c) and IL-Ra+ cells (d). e IHC Double staining showing co-localization of IL-1Ra to CD45+ microglial-like cells in the peri-infarct tissue 24 h post-stroke. f IHC score of the intensity of the IL-1Ra staining in infarct, peri-infarct and normal-appearing brain tissue. Scale bars 10 µm (a, b, e), and 50 µm (c, d)
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Fig7: IL-1Ra production in the human stroke brain. a–d IHC showing IL-1Ra+ cells in the peri-infarct (a) and infarct core (b), 24 h after stroke onset. c, d IHC staining of parallel sections showing the IgG2a isotype control (c) and IL-Ra+ cells (d). e IHC Double staining showing co-localization of IL-1Ra to CD45+ microglial-like cells in the peri-infarct tissue 24 h post-stroke. f IHC score of the intensity of the IL-1Ra staining in infarct, peri-infarct and normal-appearing brain tissue. Scale bars 10 µm (a, b, e), and 50 µm (c, d)

Mentions: Despite evidence that IL-1Ra is an important neuroprotective cytokine, its presence in the human brain after a stroke has not yet been investigated. Here, we show that IL-1Ra+ cells are present both in the peri-infarct (Fig. 7a) and the infarct core (Fig. 7b) 24 h after stroke onset (Fig. 7a–e). Scoring of IL-1Ra expression in three distinct regions, e.g., infarct core, peri-infarct and normal-appearing tissue, showed higher IL-1Ra expression in the peri-infarct compared to infarct core both 1–2 days (P < 0.04) and 5 to ≥7 days (P < 0.03) post-stroke (Fig. 7f). At ≥7 days, there was a marked increase of IL-1Ra+ cells (Table S2). Regions of infarct core, peri-infarct and normal-appearing tissue were identified based on parallel series of HE-stained sections. Iba1, CD45, CD68 and GFAP were used to distinguish the topography of IL-1Ra+ cells (Figure S7). IHC double staining showed IL-1Ra and CD45 co-expressing microglia 24 h post-stroke (Fig. 7e). These results provide novel insight into the production of IL-1Ra in the human brain and emphasize the translational relevance of our experimental results.Fig. 7


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

Clausen BH, Lambertsen KL, Dagnæs-Hansen F, Babcock AA, von Linstow CU, Meldgaard M, Kristensen BW, Deierborg T, Finsen B - Acta Neuropathol. (2016)

IL-1Ra production in the human stroke brain. a–d IHC showing IL-1Ra+ cells in the peri-infarct (a) and infarct core (b), 24 h after stroke onset. c, d IHC staining of parallel sections showing the IgG2a isotype control (c) and IL-Ra+ cells (d). e IHC Double staining showing co-localization of IL-1Ra to CD45+ microglial-like cells in the peri-infarct tissue 24 h post-stroke. f IHC score of the intensity of the IL-1Ra staining in infarct, peri-infarct and normal-appearing brain tissue. Scale bars 10 µm (a, b, e), and 50 µm (c, d)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835531&req=5

Fig7: IL-1Ra production in the human stroke brain. a–d IHC showing IL-1Ra+ cells in the peri-infarct (a) and infarct core (b), 24 h after stroke onset. c, d IHC staining of parallel sections showing the IgG2a isotype control (c) and IL-Ra+ cells (d). e IHC Double staining showing co-localization of IL-1Ra to CD45+ microglial-like cells in the peri-infarct tissue 24 h post-stroke. f IHC score of the intensity of the IL-1Ra staining in infarct, peri-infarct and normal-appearing brain tissue. Scale bars 10 µm (a, b, e), and 50 µm (c, d)
Mentions: Despite evidence that IL-1Ra is an important neuroprotective cytokine, its presence in the human brain after a stroke has not yet been investigated. Here, we show that IL-1Ra+ cells are present both in the peri-infarct (Fig. 7a) and the infarct core (Fig. 7b) 24 h after stroke onset (Fig. 7a–e). Scoring of IL-1Ra expression in three distinct regions, e.g., infarct core, peri-infarct and normal-appearing tissue, showed higher IL-1Ra expression in the peri-infarct compared to infarct core both 1–2 days (P < 0.04) and 5 to ≥7 days (P < 0.03) post-stroke (Fig. 7f). At ≥7 days, there was a marked increase of IL-1Ra+ cells (Table S2). Regions of infarct core, peri-infarct and normal-appearing tissue were identified based on parallel series of HE-stained sections. Iba1, CD45, CD68 and GFAP were used to distinguish the topography of IL-1Ra+ cells (Figure S7). IHC double staining showed IL-1Ra and CD45 co-expressing microglia 24 h post-stroke (Fig. 7e). These results provide novel insight into the production of IL-1Ra in the human brain and emphasize the translational relevance of our experimental results.Fig. 7

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winsloewsvej 25, 5000, Odense C, Denmark. bclausen@health.sdu.dk.

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.

No MeSH data available.


Related in: MedlinePlus