Interleukin 13 on Microglia is Neurotoxic in Lipopolysaccharide-injected Striatum in vivo

다국어 초록 (Multilingual Abstract)

To explore the potential function of interleukin-13 (IL-13), lipopolysaccharide (LPS) or PBS as a control was unilaterally microinjected into striatum of rat brain. Seven days after LPS injection, there was a significant loss of neurons and microglial activation in the striatum, visualized by immunohistochemical staining against neuronal nuclei (NeuN) and the OX-42 (complement receptor type 3, CR3), respectively. In parallel, IL-13 immunoreactivity was increased as early as 3 days and sustained up to 7 days post LPS injection, compared to PBS-injected control and detected exclusively within microglia. Moreover, GFAP immunostaining and blood brain barrier (BBB) permeability evaluation showed the loss of astro- cytes and disruption of BBB, respectively. By contrast, treatment with IL-13 neutralizing antibody (IL-13NA) protects NeuN+ neurons against LPS- induced neurotoxicity in vivo . Accompanying neuroprotection, IL-13NA reduced loss of GFAP+ astrocytes and damage of BBB in LPS-injected striatum. Intriguingly, treatment with IL-13NA produced neurotrophic factors (NTFs) on survived astrocytes in LPS-injected rat striatum. Taken together, the present study suggests that LPS induces expression of IL-13 on microglia, which contributes to neurodegeneration via damage on as- trocytes and BBB disruption in the striatum in vivo .

참고문헌 (Reference)

1 Kim KI, "p70S6K on astrocytes protects dopamine neurons from 1-methyl-4-phenylpyridinium neurotoxicity" 69 : 2133-2145, 2021

2 Shen Y, "Upregulation of mesencephalic astrocytederived neurotrophic factor in glial cells is associated with ischemia-induced glial activation" 9 : 254-, 2012

3 Yang G, "Therapeutic dosing with anti-interleukin-13monoclonal antibody inhibits asthma progression in mice" 313 : 8-15, 2005

4 정영철 ; 고혁완 ; 복유진 ; 허수희 ; 남진한 ; 진병관, "The role of neuroinflammation on the pathogenesis of Parkinson’s disease" 생화학분자생물학회 43 (43): 225-232, 2010

5 Giovannoni F, "The role of astrocytes in CNS inflammation" 41 : 805-819, 2020

6 Azimzadeh M, "The immunoregulatory and neuroprotective effects of human adipose derived stem cells overexpressing IL-11 and IL-13 in the experimental autoimmune encephalomyelitis mice" 87 : 106808-, 2020

7 Zlokovic BV, "The blood-brain barrier in health and chronic neurodegenerative disorders" 57 : 178-201, 2008

8 Hamzei Taj S, "Targeted intracerebral delivery of the anti-inflammatory cytokine IL13 promotes alternative activation of both microglia and macrophages after stroke" 15 : 174-, 2018

9 Nam JH, "TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson's disease via CNTF" 138 (138): 3610-3622, 2015

10 Choi DY, "Striatal neuroinflammation promotes Parkinsonism in rats" 4 : e5482-, 2009

11 Gray MT, "Striatal blood-brain barrier permeability in Parkinson's disease" 35 : 747-750, 2015

12 Espinosa-Oliva AM, "Role of dopamine in the recruitment of immune cells to the nigro-striatal dopaminergic structures" 41 : 89-101, 2014

13 Udovin L, "Role of astrocytic dysfunction in the pathogenesis of Parkinson's disease animal models from a molecular signaling perspective" 2020 : 1859431-, 2020

14 Fujimoto T, "Pitavastatin ameliorates lipopolysaccharide-induced blood-brain barrier dysfunction" 9 : 837-, 2021

15 Verkhratsky A, "Physiology of astroglia" 98 : 239-389, 2018

16 Huang X, "Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms" 27 : 36-47, 2021

17 Kolosowska N, "Peripheral administration of IL-13 induces anti-inflammatory microglial/macrophage responses and provides neuroprotection in ischemic stroke" 16 : 1304-1319, 2019

18 Lindholm P, "Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo" 448 : 73-77, 2007

19 Quarta A, "Neuroprotective modulation of microglia effector functions following priming with interleukin 4 and 13: current limitations in understanding their mode-of-action" 88 : 856-866, 2020

20 Kim DW, "Neuroprotection of ischemic preconditioning is mediated by anti-inflammatory, not pro-inflammatory, cytokines in the gerbil hippocampus induced by a subsequent lethal transient cerebral ischemia" 40 : 1984-1995, 2015

21 Farmen K, "Neuronal damage and neuroinflammation, a bridge between bacterial meningitis and neurodegenerative diseases" 15 : 680858-, 2021

22 Leng F, "Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?" 17 : 157-172, 2021

23 Mori S, "Neuroimmunology of the interleukins 13 and 4" 6 : 18-, 2016

24 Kim GW, "Neurodegeneration in striatum induced by the mitochondrial toxin 3-nitropropionic acid: role of matrix metalloproteinase-9 in early blood-brain barrier disruption?" 23 : 8733-8742, 2003

25 복유진 ; 정영철 ; 김기석 ; 백형환 ; 신원호 ; 진병관, "Modulation of M1/M2 polarization by capsaicin contributes to the survival of dopaminergic neurons in the lipopolysaccharide-lesioned substantia nigra in vivo" 생화학분자생물학회 50 : 1-14, 2018

26 Aguzzi A, "Microglia in prion diseases" 127 : 3230-3239, 2017

27 Afridi R, "Microglia gone awry: linking immunometabolism to neurodegeneration" 14 : 246-, 2020

28 Shin WH, "Microglia expressing interleukin-13 undergo cell death and contribute to neuronal survival in vivo" 46 : 142-152, 2004

29 Cash E, "Macrophage-inactivating IL-13 suppresses experimental autoimmune encephalomyelitis in rats" 153 : 4258-4267, 1994

30 Bosurgi L, "Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells" 356 : 1072-1076, 2017

31 Lee TK, "Longterm alternating fasting increases interleukin-13 in the gerbil hippocampus, but does not protect BBB and pyramidal neurons from ischemia-reperfusion injury" 45 : 2352-2363, 2020

32 Banks WA, "Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit" 12 : 223-, 2015

33 Deng I, "Lipopolysaccharide animal models of Parkinson's disease : recent progress and relevance to clinical disease" 4 : 100060-, 2020

34 Mori S, "Lack of interleukin-13 receptor α1 delays the loss of dopaminergic neurons during chronic stress" 14 : 88-, 2017

35 Aly AE, "Intranasal delivery of pGDNF DNA nanoparticles provides neuroprotection in the rat 6-hydroxydopamine model of Parkinson's disease" 56 : 688-701, 2019

36 Kawahara K, "Intracerebral microinjection of interleukin-4/interleukin-13 reduces β-amyloid accumulation in the ipsilateral side and improves cognitive deficits in young amyloid precursor protein 23 mice" 207 : 243-260, 2012

37 Chung YC, "Interleukin-4-mediated oxidative stress is harmful to hippocampal neurons of prothrombin kringle-2-lesioned rat in vivo" 9 : 1068-, 2020

38 Van Dyken SJ, "Interleukin-4- and interleukin-13-mediated alternatively activated macrophages:roles in homeostasis and disease" 31 : 317-343, 2013

39 Jeong JY, "Interleukin-4 and interleukin-13 exacerbate neurotoxicity of prothrombin kringle-2in cortex in vivo via oxidative stress" 20 : 1927-, 2019

40 복유진 ; 조은주 ; 정은숙 ; 신원호 ; 진병관, "Interleukin-4 Contributes to Degeneration of Dopamine Neurons in the Lipopolysaccharidetreated Substantia Nigra in vivo" 한국뇌신경과학회 27 (27): 309-319, 2018

41 Jeong JY, "Interleukin-13propagates prothrombin kringle-2-induced neurotoxicity in hippocampi in vivo via oxidative stress" 22 : 3486-, 2021

42 Nam JH, "Interleukin-13/-4-induced oxidative stress contributes to death of hippocampal neurons in aβ1-42-treated hippocampus in vivo" 16 : 1369-1383, 2012

43 Huang L, "Interleukin-13 gene modification enhances grafted mesenchymal stem cells survival after subretinal transplantation" 40 : 725-735, 2020

44 Logsdon AF, "Inter-alpha inhibitor proteins attenuate lipopolysaccharide-induced blood-brain barrier disruption and downregulate circulating interleukin 6 in mice" 40 : 1090-1102, 2020

45 Baek JY, "Inhibition of microglia-derived oxidative stress by ciliary neurotrophic factor protects dopamine neurons in vivo from MPP+ neurotoxicity" 19 : 3543-, 2018

46 Hunter RL, "Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system" 100 : 1375-1386, 2007

47 Zhang MZ, "IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury" 91 : 375-386, 2017

48 Sinha S, "IL-13-mediated gender difference in susceptibility to autoimmune encephalomyelitis" 180 : 2679-2685, 2008

49 Park KW, "IL-13-induced oxidative stress via microglial NADPH oxidase contributes to death of hippocampal neurons in vivo" 183 : 4666-4674, 2009

50 Miao W, "IL-13 ameliorates neuroinflammation and promotes functional recovery after traumatic brain injury" 204 : 1486-1498, 2020

51 Wispelwey B, "Haemophilus influenzae lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat" 82 : 1339-1346, 1988

52 Hoban DB, "Further characterisation of the LPS model of Parkinson's disease:a comparison of intra-nigral and intra-striatal lipopolysaccharide administration on motor function, microgliosis and nigrostriatal neurodegeneration in the rat" 27 : 91-100, 2013

53 Matsukawa A, "Expression and contribution of endogenous IL-13 in an experimental model of sepsis" 164 : 2738-2744, 2000

54 김경인 ; 백정엽 ; 정재영 ; 남진한 ; 박은수 ; 복유진 ; 신원호 ; 정영철 ; 진병관, "Delayed Treatment of Capsaicin Produces Partial Motor Recovery by Enhancing Dopamine Function in MPP+-lesioned Rats via Ciliary Neurotrophic Factor" 한국뇌신경과학회 28 (28): 289-299, 2019

55 Sengillo JD, "Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease" 23 : 303-310, 2013

56 Morrison BE, "Cutting edge : IL-13Rα1 expression in dopaminergic neurons contributes to their oxidative stress-mediated loss following chronic peripheral treatment with lipopolysaccharide" 189 : 5498-5502, 2012

57 Fischer D, "Crystallins of the beta/gamma-superfamily mimic the effects of lens injury and promote axon regeneration" 37 : 471-479, 2008

58 Lee CH, "Comparison of neuronal death, blood-brain barrier leakage and inflammatory cytokine expression in the hippocampal CA1 region following mild and severe transient forebrain ischemia in gerbils" 46 : 2852-2866, 2021

59 Bluthé RM, "Central injection of interleukin-13 potentiates LPS-induced sickness behavior in rats" 12 : 3979-3983, 2001

60 Popovich PG, "Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats" 377 : 443-464, 1997

61 Cabezas R, "Astrocytic modulation of blood brain barrier : perspectives on Parkinson's disease" 8 : 211-, 2014

62 Linnerbauer M, "Astrocyte crosstalk in CNS inflammation" 108 : 608-622, 2020

63 Yang G, "Anti-IL-13monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling" 28 : 224-232, 2004

64 Tucsek Z, "Aging exacerbates obesityinduced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice" 69 : 1339-1352, 2014