CoChat
Sign Up
Cited by 35Neonatal and fetal brain pathologyNeuroinflammation and Neurodegeneration MechanismsTraumatic Brain Injury and Neurovascular Disturbances

Rh‐CSF1 attenuates neuroinflammation via the CSF1R/PLCG2/PKCε pathway in a rat model of neonatal HIE

Open access
Hu, Xiao, Li, Shirong, Doycheva, Desislava Met, Huang, Lei, Lenahan, Cameron, Liu, Rui, Huang, Juan, Xie, Shucai +3 more·2020·Journal of Neuroinflammation
DOI 10.1186/s12974-020-01862-wPMC PMC7285566
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: Hypoxic-ischemic encephalopathy (HIE) is a life-threatening cerebrovascular disease. Neuroinflammation plays an important role in the pathogenesis of HIE, in which microglia are key cellular mediators in the regulation of neuroinflammatory processes. Colony-stimulating factor 1 (CSF1), a specific endogenous ligand of CSF1 receptor (CSF1R), is crucial in microglial growth, differentiation, and proliferation. Recent studies showed that the activation of CSF1R with CSF1 exerted anti-inflammatory effects in a variety of nervous system diseases. This study aimed to investigate the anti-inflammatory effects of recombinant human CSF1 (rh-CSF1) and the underlying mechanisms in a rat model of HIE. Methods: A total of 202 10-day old Sprague Dawley rat pups were used. HI was induced by the right common carotid artery ligation with subsequent exposure of 2.5-h hypoxia. At 1 h and 24 h after HI induction, exogenous rh-CSF1 was administered intranasally. To explore the underlying mechanism, CSF1R inhibitor, BLZ945, and phospholipase C-gamma 2 (PLCG2) inhibitor, U73122, were injected intraperitoneally at 1 h before HI induction, respectively. Brain infarct area, brain water content, neurobehavioral tests, western blot, and immunofluorescence staining were performed. Results: The expressions of endogenous CSF1, CSF1R, PLCG2, protein kinase C epsilon type (PKCε), and cAMP response element-binding protein (CREB) were gradually increased after HIE. Rh-CSF1 significantly improved the neurological deficits at 48 h and 4 weeks after HI, which was accompanied by a reduction in the brain infarct area, brain edema, brain atrophy, and neuroinflammation. Moreover, activation of CSF1R by rh-CSF1 significantly increased the expressions of p-PLCG2, p-PKCε, and p-CREB, but inhibited the activation of neutrophil infiltration, and downregulated the expressions of IL-1β and TNF-α. Inhibition of CSF1R and PLCG2 abolished these neuroprotective effects of rh-CSF1 after HI. Conclusions: Our findings demonstrated that the activation of CSF1R by rh-CSF1 attenuated neuroinflammation and improved neurological deficits after HI. The anti-inflammatory effects of rh-CSF1 partially acted through activating the CSF1R/PLCG2/PKCε/CREB signaling pathway after HI. These results suggest that rh-CSF1 may serve as a potential therapeutic approach to ameliorate injury in HIE patients.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s12974-020-01862-w

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 81 · Cited by 35

Research works printed but not linked: 64

  1. [1]McDonald CA Djuliannisaa Z Petraki M Paton MCB Penny TR Sutherland AE Intranasal delivery of mesenchymal stromal cells protects against neonatal hypoxic(-)ischemic brain injury Int J Mol Sci 2019 20 10 2449 PMC6566762 31108944
  2. [2]Abbasi H Gunn AJ Bennet L Unsworth CP Latent phase identification of high-frequency micro-scale gamma spike transients in the hypoxic ischemic EEG of preterm fetal sheep using spectral analysis and fuzzy classifiers sensors (Basel) 2020 20 5 1424 PMC7085637 32150987
  3. [3]Li M Cui MM Kenechukwu NA Gu YW Chen YL Zhong SJ Rosmarinic acid ameliorates hypoxia/ischemia induced cognitive deficits and promotes remyelination Neural Regen Res 2020 15 5 894 902 31719255 PMC6990785
  4. [4]Douglas-Escobar M Weiss MD Hypoxic-ischemic encephalopathy: a review for the clinician JAMA Pediatr 2015 169 4 397 403 25685948
  5. [5]Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia. JAMA Pediatr. 2019. PMC6865301 31710357
  6. [6]Herrera TI Edwards L Malcolm WF Smith PB Fisher KA Pizoli C Outcomes of preterm infants treated with hypothermia for hypoxic-ischemic encephalopathy Early Hum Dev 2018 125 1 7 30144709
  7. [7]Easley-Neal C Foreman O Sharma N Zarrin AA Weimer RM CSF1R ligands IL-34 and CSF1 are differentially required for microglia development and maintenance in white and gray matter brain regions Front Immunol 2019 10 2199 31616414 PMC6764286
  8. [8]Wu Z Harne R Chintoan-Uta C Hu TJ Wallace R MacCallum A Regulation and function of macrophage colony-stimulating factor (CSF1) in the chicken immune system Dev Comp Immunol 2020 105 103586 31870792 PMC6996135
  9. [9]Chitu V Gokhan S Nandi S Mehler MF Stanley ER Emerging roles for CSF-1 receptor and its ligands in the nervous system Trends Neurosci 2016 39 6 378 393 27083478 PMC4884457
  10. [10]Kierdorf K Prinz M Microglia: same same, but different J Exp Med 2019 216 10 2223 2225 31527071 PMC6781008
  11. [11]Wylot B, Mieczkowski J, Niedziolka S, Kaminska B, Zawadzka M. Csf1 Deficiency dysregulates glial responses to demyelination and disturbs CNS white matter remyelination. Cells. 2019;9(1) 99. PMC7017166 31906095
  12. [12]Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014;6(6). PMC4031967 24890514
  13. [13]Xu Q Malecka KL Fink L Jordan EJ Duffy E Kolander S Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases Sci Signal 2015 8 405 rs13 26628682 PMC4766099
  14. [15]Luo J Elwood F Britschgi M Villeda S Zhang H Ding Z Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival J Exp Med 2013 210 1 157 172 23296467 PMC3549715
  15. [16]Chen Z Hu Y Lu R Ge M Zhang L MicroRNA-374a-5p inhibits neuroinflammation in neonatal hypoxic-ischemic encephalopathy via regulating NLRP3 inflammasome targeted Smad6 Life Sci 2020 252 117664 32304765
  16. [17]Yenari MA Kauppinen TM Swanson RA Microglial activation in stroke: therapeutic targets Neurotherapeutics. 2010 7 4 378 391 20880502 PMC5084300
  17. [18]Chu F Shi M Zheng C Shen D Zhu J Zheng X The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis J Neuroimmunol 2018 318 1 7 29606295
  18. [21]Lin W Xu D Austin CD Caplazi P Senger K Sun Y Function of CSF1 and IL34 in macrophage homeostasis, inflammation, and cancer Front Immunol 2019 10 2019 31552020 PMC6736990
  19. [23]Irons DL Meinhardt T Allers C Kuroda MJ Kim WK Overexpression and activation of colony-stimulating factor 1 receptor in the SIV/macaque model of HIV infection and neuroHIV Brain Pathol 2019 29 6 826 836 31033097 PMC6810716
  20. [27]Barbosa CM Bincoletto C Barros CC Ferreira AT Paredes-Gamero EJ PLCgamma2 and PKC are important to myeloid lineage commitment triggered by M-SCF and G-CSF J Cell Biochem 2014 115 1 42 51 24038146
  21. [28]Obba S Hizir Z Boyer L Selimoglu-Buet D Pfeifer A Michel G The PRKAA1/AMPKalpha1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML Autophagy. 2015 11 7 1114 1129 26029847 PMC4590592
  22. [30]Cheeseman KL Ueyama T Michaud TM Kashiwagi K Wang D Flax LA Targeting of protein kinase C-epsilon during Fcgamma receptor-dependent phagocytosis requires the epsilonC1B domain and phospholipase C-gamma1 Mol Biol Cell 2006 17 2 799 813 16319178 PMC1356590
  23. [31]Nakamura Y Fukami K Regulation and physiological functions of mammalian phospholipase C J Biochem 2017 161 4 315 321 28130414
  24. [32]Kumar V Weng YC Wu YC Huang YT Chou WH PKCepsilon phosphorylation regulates the mitochondrial translocation of ATF2 in ischemia-induced neurodegeneration BMC Neurosci 2018 19 1 76 30497386 PMC6267029
  25. [33]Zuo G Zhang T Huang L Araujo C Peng J Travis Z Activation of TGR5 with INT-777 attenuates oxidative stress and neuronal apoptosis via cAMP/PKCepsilon/ALDH2 pathway after subarachnoid hemorrhage in rats Free Radic Biol Med 2019 143 441 453 31493504 PMC6848789
  26. [34]Gessi S Borea PA Bencivenni S Fazzi D Varani K Merighi S The activation of mu-opioid receptor potentiates LPS-induced NF-kB promoting an inflammatory phenotype in microglia FEBS Lett 2016 590 17 2813 2826 27427408
  27. [35]Derouiche A Geiger KD Perspectives for Ezrin and radixin in astrocytes: kinases, functions and pathology Int J Mol Sci 2019 20 15 3776 PMC6695708 31382374
  28. [36]Mylroie H Dumont O Bauer A Thornton CC Mackey J Calay D PKCepsilon-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis Cardiovasc Res 2015 106 3 509 519 25883219 PMC4431664
  29. [37]Guan X Wang Y Kai G Zhao S Huang T Li Y Cerebrolysin ameliorates focal cerebral ischemia injury through neuroinflammatory inhibition via CREB/PGC-1alpha pathway Front Pharmacol 2019 10 1245 31695614 PMC6818051
  30. [38]Jaworska J Zalewska T Sypecka J Ziemka-Nalecz M Effect of the HDAC inhibitor, sodium butyrate, on neurogenesis in a rat model of neonatal hypoxia-ischemia: potential mechanism of action Mol Neurobiol 2019 56 9 6341 6370 30767185 PMC6682584
  31. [39]Rice JE 3rd Vannucci RC Brierley JB The influence of immaturity on hypoxic-ischemic brain damage in the rat Ann Neurol 1981 9 2 131 141 7235629
  32. [40]Dock H Theodorsson A Theodorsson E DNA methylation inhibitor Zebularine confers stroke protection in ischemic rats Transl Stroke Res 2015 6 4 296 300 25824538
  33. [41]Wang Z Zhou F Dou Y Tian X Liu C Li H Melatonin alleviates intracerebral hemorrhage-induced secondary brain injury in rats via suppressing apoptosis, inflammation, oxidative stress, DNA damage, and mitochondria injury Transl Stroke Res 2018 9 1 74 91 28766251 PMC5750335
  34. [42]Tanaka M Ogaeri T Samsonov M Sokabe M The 5alpha-reductase inhibitor finasteride exerts neuroprotection against ischemic brain injury in aged male rats Transl Stroke Res 2019 10 1 67 77 29574659
  35. [43]Griemert EV Recarte Pelz K Engelhard K Schafer MK Thal SC PAI-1 but not PAI-2 gene deficiency attenuates ischemic brain injury after experimental stroke Transl Stroke Res 2019 10 4 372 380 29978354 PMC6647425
  36. [44]Liu H Hua Y Keep RF Xi G Brain ceruloplasmin expression after experimental intracerebral hemorrhage and protection against iron-induced brain injury Transl Stroke Res 2019 10 1 112 119 30315404 PMC6438204
  37. [45]Zhang Y, Zhang X, Wei Q, Leng S, Li C, Han B, et al. Activation of sigma-1 receptor enhanced pericyte survival via the interplay between apoptosis and autophagy: implications for blood-brain barrier integrity in stroke. Transl Stroke Res. 2019. 31290080
  38. [46]Walker DG Tang TM Lue LF Studies on colony stimulating factor receptor-1 and ligands colony stimulating factor-1 and interleukin-34 in Alzheimer's disease brains and human microglia Front Aging Neurosci 2017 9 244 28848420 PMC5552759
  39. [47]Borjini N Fernandez M Giardino L Calza L Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis J Neuroinflammation 2016 13 1 291 27846891 PMC5111339
  40. [48]Knight AC Brill SA Queen SE Tarwater PM Mankowski JL Increased microglial CSF1R expression in the SIV/macaque model of HIV CNS disease J Neuropathol Exp Neurol 2018 77 3 199 206 29319809 PMC6251515
  41. [50]Liu X Ma Y Wei X Fan T Neuroprotective effect of licochalcone a against oxygen-glucose deprivation/reperfusion in rat primary cortical neurons by attenuating oxidative stress injury and inflammatory response via the SIRT1/Nrf2 pathway J Cell Biochem 2018 119 4 3210 3219 29105819
  42. [51]Chauhan MB Chauhan NB Brain uptake of Neurotherapeutics after intranasal versus intraperitoneal delivery in mice J Neurol Neurosurg 2015 2 1 009 26366437 PMC4567259
  43. [52]Byeon JH Kim GH Kim JY Sun W Kim H Eun BL Cognitive dysfunction and hippocampal damage induced by hypoxic-ischemic brain injury and prolonged febrile convulsions in immature rats J Korean Neurosurg Soc 2015 58 1 22 29 26279809 PMC4534735
  44. [53]Herold F Torpel A Schega L Muller NG Functional and/or structural brain changes in response to resistance exercises and resistance training lead to cognitive improvements - a systematic review Eur Rev Aging Phys Act 2019 16 10 31333805 PMC6617693
  45. [55]Raivich G Haas S Werner A Klein MA Kloss C Kreutzberg GW Regulation of MCSF receptors on microglia in the normal and injured mouse central nervous system: a quantitative immunofluorescence study using confocal laser microscopy J Comp Neurol 1998 395 3 342 358 9596528
  46. [56]De I Nikodemova M Steffen MD Sokn E Maklakova VI Watters JJ CSF1 overexpression has pleiotropic effects on microglia in vivo Glia. 2014 62 12 1955 1967 25042473 PMC4205273
  47. [57]Chang KH Wu YR Chen YC Wu HC Chen CM Association between CSF1 and CSF1R polymorphisms and Parkinson's disease in Taiwan J Clin Med 2019 8 10 1529 PMC6832167 31554150
  48. [58]Horti AG Naik R Foss CA Minn I Misheneva V Du Y PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R) Proc Natl Acad Sci U S A 2019 116 5 1686 1691 30635412 PMC6358677
  49. [60]Fleetwood AJ Lawrence T Hamilton JA Cook AD Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation J Immunol 2007 178 8 5245 5252 17404308
  50. [61]Pepe G De Maglie M Minoli L Villa A Maggi A Vegeto E Selective proliferative response of microglia to alternative polarization signals J Neuroinflammation 2017 14 1 236 29202771 PMC5715534
  51. [62]Miao Y He T Zhu Y Li W Wang B Zhong Y Activation of hippocampal CREB by rolipram partially recovers balance between TNF-alpha and IL-10 levels and improves cognitive deficits in diabetic rats Cell Mol Neurobiol 2015 35 8 1157 1164 26001770 PMC11488058
  52. [63]Hu BR Fux CM Martone ME Zivin JA Ellisman MH Persistent phosphorylation of cyclic AMP responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain Neuroscience. 1999 89 2 437 452 10077326
  53. [64]Hung PL Hsu MH Yu HR Wu KLH Wang FS Thyroxin protects white matter from hypoxic-ischemic insult in the immature Sprague(-)Dawley rat brain by regulating periventricular white matter and cortex BDNF and CREB pathways Int J Mol Sci 2018 19 9 2573 PMC6164053 30158497
  54. [67]Gotwals P Cameron S Cipolletta D Cremasco V Crystal A Hewes B Prospects for combining targeted and conventional cancer therapy with immunotherapy Nat Rev Cancer 2017 17 5 286 301 28338065
  55. [68]Gilbert DF Stebbing MJ Kuenzel K Murphy RM Zacharewicz E Buttgereit A Store-operated ca(2+) entry (SOCE) and purinergic receptor-mediated ca(2+) homeostasis in murine bv2 microglia cells: early cellular responses to ATP-mediated microglia activation Front Mol Neurosci 2016 9 111 27840602 PMC5083710
  56. [70]Zhu L Jones C Zhang G The role of phospholipase C signaling in macrophage-mediated inflammatory response J Immunol Res 2018 2018 5201759 30057916 PMC6051040
  57. [71]Waza AA Andrabi K Hussain MU Protein kinase C (PKC) mediated interaction between conexin43 (Cx43) and K(+)(ATP) channel subunit (Kir6.1) in cardiomyocyte mitochondria: implications in cytoprotection against hypoxia induced cell apoptosis Cell Signal 2014 26 9 1909 1917 24815185
  58. [72]Surendran D PKCgamma and PKCepsilon are differentially activated and modulate neurotoxic signaling pathways during oxygen glucose deprivation in rat cortical slices Neurochem Res 2019 44 11 2577 2589 31541352
  59. [73]Liu F McCullough LD Inflammatory responses in hypoxic ischemic encephalopathy Acta Pharmacol Sin 2013 34 9 1121 1130 23892271 PMC3764334
  60. [74]Al Mamun A Yu H Mirza MA Romana S McCullough LD Liu F Myeloid cell IRF4 signaling protects neonatal brains from hypoxic ischemic encephalopathy Neurochem Int 2019 127 148 157 30586599 PMC6579623
  61. [75]Del Bigio MR Becker LE Microglial aggregation in the dentate gyrus: a marker of mild hypoxic-ischaemic brain insult in human infants Neuropathol Appl Neurobiol 1994 20 2 144 151 8072645
  62. [76]Rawlinson C Jenkins S Thei L Dallas ML Chen R Post-ischaemic immunological response in the brain: targeting microglia in ischaemic stroke therapy Brain Sci 2020 10 3 159 PMC7139954 32168831
  63. [77]Tsuji S Di Martino E Mukai T Tsuji S Murakami T Harris RA Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice J Neuroinflammation 2020 17 1 111 32276642 PMC7149909
  64. [78]Chitu V Stanley ER Regulation of embryonic and postnatal development by the CSF-1 receptor Curr Top Dev Biol 2017 123 229 275 28236968 PMC5479137

Authors
Hu, X., Li, S., Doycheva, D. M., Huang, L., Lenahan, C., Liu, R., Huang, J., Xie, S., Tang, J., Zuo, G., & Zhang, J. H.
Affiliations
  • Loma Linda University (US)
  • Central South University (CN)
Corresponding author
  • Zuo, Gang
  • Zhang, John H.
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2020-06-10
Volume
17
Issue
1
Pages
182-182
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-020-01862-w
PMC
PMC7285566
OpenAlex
W3033947439
Cited by
35
References
81
Citations by year
2026: 4 · 2025: 6 · 2024: 6 · 2023: 3 · 2022: 7 · 2021: 6 · 2020: 1 · 2019: 1 · 2018: 1
FWCI
4.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (NS104083)
  • National Natural Science Foundation of China (81601051)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
hypoxic-ischemic encephalopathy, neuroinflammation, CSF1R, PLCγ2, protein kinase C epsilon, CREB, microglia, neuroprotection, neonatal brain injury, intranasal drug delivery, neutrophil infiltration, IL-1β, TNF-α, BLZ945
MeSH terms
Animals, Animals, Newborn, Humans, Inflammation, Recombinant Proteins, Signal Transduction, Macrophage Colony-Stimulating Factor, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Rats, Sprague-Dawley, Neuroprotective Agents, Hypoxia-Ischemia, Brain, Rats, Protein Kinase C-epsilon, Phospholipase C gamma

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review