Limits...
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

Endogenous IL-1Ra is neuroprotective. (a, b) Infarct volume estimated in LM and IL-1Ra-KO (KO) mice (a), and in LM  and IL-1Ra-Tg (Tg) mice (b), 24 h after pMCAo, with toluidine blue staining of the ischemic infarct, n = 14/group. Statistical data are presented as mean ± SD (Mann–Whitney test). *P < 0.05; **P < 0.01. c, dISH showing IL-1Ra mRNA+ cells (arrows in c) and IHC showing IL-1Ra+ cells (arrows in d) in the peri-infarct 24 h after pMCAo. cc corpus callosum; IF infarct; P-IF peri-infarct; Str striatum. Scale bars 1 mm (a, b), and 100 µm (c, d)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4835531&req=5

Fig1: Endogenous IL-1Ra is neuroprotective. (a, b) Infarct volume estimated in LM and IL-1Ra-KO (KO) mice (a), and in LM  and IL-1Ra-Tg (Tg) mice (b), 24 h after pMCAo, with toluidine blue staining of the ischemic infarct, n = 14/group. Statistical data are presented as mean ± SD (Mann–Whitney test). *P < 0.05; **P < 0.01. c, dISH showing IL-1Ra mRNA+ cells (arrows in c) and IHC showing IL-1Ra+ cells (arrows in d) in the peri-infarct 24 h after pMCAo. cc corpus callosum; IF infarct; P-IF peri-infarct; Str striatum. Scale bars 1 mm (a, b), and 100 µm (c, d)

Mentions: To confirm the findings by others suggesting that endogenous IL-1Ra is neuroprotective in experimental stroke [43], we initially subjected IL-1Ra knockout (IL-1Ra-KO) mice, mice overproducing IL-1Ra under the control of the natural promoter (IL-1Ra-Tg) and their respective littermate (LM) mice to permanent middle cerebral artery (MCA) occlusion (pMCAo) (Table S1). Twenty-four hours after pMCAo, IL-1Ra-KO mice developed significantly larger infarcts (Fig. 1a) and IL-1Ra-Tg mice significantly smaller infarcts (Fig. 1b) than their respective LM controls. Additionally, at 24 h after pMCAo, we observed numerous IL-1Ra mRNA expressing (IL-1Ra mRNA+) cells, and IL-1Ra immunoreactive (IL-1Ra+) cells within the peri-infarct in C57BL/6 mice (Fig. 1c, d). The location of the IL-1Ra-producing cells in the tissue at risk for degeneration is consistent with a neuroprotective role of endogenous IL-1Ra.Fig. 1


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)

Endogenous IL-1Ra is neuroprotective. (a, b) Infarct volume estimated in LM and IL-1Ra-KO (KO) mice (a), and in LM  and IL-1Ra-Tg (Tg) mice (b), 24 h after pMCAo, with toluidine blue staining of the ischemic infarct, n = 14/group. Statistical data are presented as mean ± SD (Mann–Whitney test). *P < 0.05; **P < 0.01. c, dISH showing IL-1Ra mRNA+ cells (arrows in c) and IHC showing IL-1Ra+ cells (arrows in d) in the peri-infarct 24 h after pMCAo. cc corpus callosum; IF infarct; P-IF peri-infarct; Str striatum. Scale bars 1 mm (a, b), and 100 µm (c, d)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Endogenous IL-1Ra is neuroprotective. (a, b) Infarct volume estimated in LM and IL-1Ra-KO (KO) mice (a), and in LM  and IL-1Ra-Tg (Tg) mice (b), 24 h after pMCAo, with toluidine blue staining of the ischemic infarct, n = 14/group. Statistical data are presented as mean ± SD (Mann–Whitney test). *P < 0.05; **P < 0.01. c, dISH showing IL-1Ra mRNA+ cells (arrows in c) and IHC showing IL-1Ra+ cells (arrows in d) in the peri-infarct 24 h after pMCAo. cc corpus callosum; IF infarct; P-IF peri-infarct; Str striatum. Scale bars 1 mm (a, b), and 100 µm (c, d)
Mentions: To confirm the findings by others suggesting that endogenous IL-1Ra is neuroprotective in experimental stroke [43], we initially subjected IL-1Ra knockout (IL-1Ra-KO) mice, mice overproducing IL-1Ra under the control of the natural promoter (IL-1Ra-Tg) and their respective littermate (LM) mice to permanent middle cerebral artery (MCA) occlusion (pMCAo) (Table S1). Twenty-four hours after pMCAo, IL-1Ra-KO mice developed significantly larger infarcts (Fig. 1a) and IL-1Ra-Tg mice significantly smaller infarcts (Fig. 1b) than their respective LM controls. Additionally, at 24 h after pMCAo, we observed numerous IL-1Ra mRNA expressing (IL-1Ra mRNA+) cells, and IL-1Ra immunoreactive (IL-1Ra+) cells within the peri-infarct in C57BL/6 mice (Fig. 1c, d). The location of the IL-1Ra-producing cells in the tissue at risk for degeneration is consistent with a neuroprotective role of endogenous IL-1Ra.Fig. 1

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