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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

Leukocyte-derived IL-1Ra reduces ischemic infarction in IL-1Ra-B6* BM chimeric mice. a Infarct volumes estimated in whole body-irradiated* C57BL/6 (B6*) mice reconstituted with BM from either B6, IL-1Ra-KO, or IL-1Ra-Tg mice, 24 h after pMCAo, n = 12–14/group. Statistical data are presented as mean ± SD (Kruskal–Wallis test with Dunns post hoc test), *P < 0.05. b, cISH for IL-1Ra mRNA of sections from IL-1Ra-KO mice showing absence of IL-1Ra mRNA+ (b), and of irradiated IL-1Ra-KO mice (KO*) reconstituted with BM from IL-1Ra-Tg mice, showing the presence of infiltrating IL-1Ra mRNA+ cells in the peri-infarct, 24 h after pMCAo (c). d, e IL-1Ra mRNA and IL-1Ra protein levels in the same groups of mice as illustrated in (b, c), and determined by qPCR (d) and ELISA (e). IF infarct; ND none detected; P-IF peri-infarct. Scale bar 100 µm
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Fig4: Leukocyte-derived IL-1Ra reduces ischemic infarction in IL-1Ra-B6* BM chimeric mice. a Infarct volumes estimated in whole body-irradiated* C57BL/6 (B6*) mice reconstituted with BM from either B6, IL-1Ra-KO, or IL-1Ra-Tg mice, 24 h after pMCAo, n = 12–14/group. Statistical data are presented as mean ± SD (Kruskal–Wallis test with Dunns post hoc test), *P < 0.05. b, cISH for IL-1Ra mRNA of sections from IL-1Ra-KO mice showing absence of IL-1Ra mRNA+ (b), and of irradiated IL-1Ra-KO mice (KO*) reconstituted with BM from IL-1Ra-Tg mice, showing the presence of infiltrating IL-1Ra mRNA+ cells in the peri-infarct, 24 h after pMCAo (c). d, e IL-1Ra mRNA and IL-1Ra protein levels in the same groups of mice as illustrated in (b, c), and determined by qPCR (d) and ELISA (e). IF infarct; ND none detected; P-IF peri-infarct. Scale bar 100 µm

Mentions: Based on the observation that IL-1Ra is expressed by a small subset of infiltrating CD11b+CD45high leukocytes, we next tested whether increasing IL-1Ra production in infiltrating leukocytes would be neuroprotective. As previously done [10, 40], we used a BM chimeric approach, comparing infarct development in whole body-irradiated recipient C57BL/6 mice (B6*) mice reconstituted with BM cells from either IL-1Ra-Tg, IL-1Ra-KO or B6 mice (Table S1). We observed no difference in infarct size between KO-B6* BM chimeric mice and B6–B6* BM chimeric mice (Fig. 4a), which indicates that leukocytes under normal conditions fail to produce sufficient IL-1Ra to influence infarct development. In comparison, the Tg–B6* BM chimeras developed significantly smaller infarcts compared to the B6–B6* BM chimeric mice, 24 h after pMCAo (Fig. 4a), suggesting that increasing the level of leukocyte-produced IL-1Ra is neuroprotective.Fig. 4


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)

Leukocyte-derived IL-1Ra reduces ischemic infarction in IL-1Ra-B6* BM chimeric mice. a Infarct volumes estimated in whole body-irradiated* C57BL/6 (B6*) mice reconstituted with BM from either B6, IL-1Ra-KO, or IL-1Ra-Tg mice, 24 h after pMCAo, n = 12–14/group. Statistical data are presented as mean ± SD (Kruskal–Wallis test with Dunns post hoc test), *P < 0.05. b, cISH for IL-1Ra mRNA of sections from IL-1Ra-KO mice showing absence of IL-1Ra mRNA+ (b), and of irradiated IL-1Ra-KO mice (KO*) reconstituted with BM from IL-1Ra-Tg mice, showing the presence of infiltrating IL-1Ra mRNA+ cells in the peri-infarct, 24 h after pMCAo (c). d, e IL-1Ra mRNA and IL-1Ra protein levels in the same groups of mice as illustrated in (b, c), and determined by qPCR (d) and ELISA (e). IF infarct; ND none detected; P-IF peri-infarct. Scale bar 100 µm
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Fig4: Leukocyte-derived IL-1Ra reduces ischemic infarction in IL-1Ra-B6* BM chimeric mice. a Infarct volumes estimated in whole body-irradiated* C57BL/6 (B6*) mice reconstituted with BM from either B6, IL-1Ra-KO, or IL-1Ra-Tg mice, 24 h after pMCAo, n = 12–14/group. Statistical data are presented as mean ± SD (Kruskal–Wallis test with Dunns post hoc test), *P < 0.05. b, cISH for IL-1Ra mRNA of sections from IL-1Ra-KO mice showing absence of IL-1Ra mRNA+ (b), and of irradiated IL-1Ra-KO mice (KO*) reconstituted with BM from IL-1Ra-Tg mice, showing the presence of infiltrating IL-1Ra mRNA+ cells in the peri-infarct, 24 h after pMCAo (c). d, e IL-1Ra mRNA and IL-1Ra protein levels in the same groups of mice as illustrated in (b, c), and determined by qPCR (d) and ELISA (e). IF infarct; ND none detected; P-IF peri-infarct. Scale bar 100 µm
Mentions: Based on the observation that IL-1Ra is expressed by a small subset of infiltrating CD11b+CD45high leukocytes, we next tested whether increasing IL-1Ra production in infiltrating leukocytes would be neuroprotective. As previously done [10, 40], we used a BM chimeric approach, comparing infarct development in whole body-irradiated recipient C57BL/6 mice (B6*) mice reconstituted with BM cells from either IL-1Ra-Tg, IL-1Ra-KO or B6 mice (Table S1). We observed no difference in infarct size between KO-B6* BM chimeric mice and B6–B6* BM chimeric mice (Fig. 4a), which indicates that leukocytes under normal conditions fail to produce sufficient IL-1Ra to influence infarct development. In comparison, the Tg–B6* BM chimeras developed significantly smaller infarcts compared to the B6–B6* BM chimeric mice, 24 h after pMCAo (Fig. 4a), suggesting that increasing the level of leukocyte-produced IL-1Ra is neuroprotective.Fig. 4

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