IQGAP2 regulates blood-brain barrier immune dynamics.
| العنوان: | IQGAP2 regulates blood-brain barrier immune dynamics. |
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| المؤلفون: | Katdare KA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA., Kjar A; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., O'Brown NM; Department of Systems Biology, Harvard Medical School, Boston, MA, USA., Neal EH; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA., Sorets AG; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Shostak A; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA., Romero-Fernandez W; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA., Kwiatkowski AJ; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA., Mlouk K; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA., Kim H; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA., Cowell RP; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA., Schwensen KR; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA., Horner KB; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA., Wilson JT; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA., Schrag MS; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA.; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA., Megason SG; Department of Systems Biology, Harvard Medical School, Boston, MA, USA., Lippmann ES; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA.; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Apr 12. Date of Electronic Publication: 2024 Apr 12. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Brain endothelial cells (BECs) play an important role in maintaining central nervous system (CNS) homeostasis through blood-brain barrier (BBB) functions. BECs express low baseline levels of adhesion receptors, which limits entry of leukocytes. However, the molecular mediators governing this phenotype remain mostly unclear. Here, we explored how infiltration of immune cells across the BBB is influenced by the scaffold protein IQ motif containing GTPase activating protein 2 (IQGAP2). In mice and zebrafish, we demonstrate that loss of Iqgap2 increases infiltration of peripheral leukocytes into the CNS under homeostatic and inflammatory conditions. Using single-cell RNA sequencing and immunohistology, we further show that BECs from mice lacking Iqgap2 exhibit a profound inflammatory signature, including extensive upregulation of adhesion receptors and antigen-processing machinery. Human tissue analyses also reveal that Alzheimer's disease is associated with reduced hippocampal IQGAP2. Overall, our results implicate IQGAP2 as an essential regulator of BBB immune privilege and immune cell entry into the CNS. Competing Interests: Competing interests The authors declare no competing interests. |
| References: | Nature. 2014 May 22;509(7501):507-11. (PMID: 24828040) Neuroscience. 2002;112(3):731-49. (PMID: 12074914) Vasc Biol. 2020 Mar 20;2(1):H1-H18. (PMID: 32923970) Nat Neurosci. 2023 Sep;26(9):1489-1504. (PMID: 37620442) Science. 2022 Mar 4;375(6584):eabi7377. (PMID: 35084939) PLoS One. 2015 Aug 07;10(8):e0133770. (PMID: 26252773) Cell Rep. 2020 Mar 31;30(13):4418-4432.e4. (PMID: 32234477) Cell Mol Immunol. 2021 Nov;18(11):2489-2501. (PMID: 34594000) Trends Neurosci. 2022 Oct;45(10):733-748. (PMID: 36075783) J Cell Biol. 2008 Nov 3;183(3):409-17. (PMID: 18955553) Nature. 2018 Feb 22;554(7693):475-480. (PMID: 29443965) Nat Immunol. 2019 Feb;20(2):163-172. (PMID: 30643263) PLoS Genet. 2021 Apr 8;17(4):e1009406. (PMID: 33830999) Vet Pathol. 2013 Jan;50(1):7-22. (PMID: 23345459) Nature. 2022 Mar;603(7903):893-899. (PMID: 35158371) Nature. 2023 Mar;615(7953):668-677. (PMID: 36890231) Science. 2015 Jan 23;347(6220):1260419. (PMID: 25613900) Trends Immunol. 2015 Oct;36(10):569-577. (PMID: 26431936) Cell. 2020 Feb 20;180(4):764-779.e20. (PMID: 32059779) J Neuroimmune Pharmacol. 2013 Sep;8(4):840-56. (PMID: 23695293) Trends Neurosci. 2005 Nov;28(11):571-3. (PMID: 16165228) J Neurosci. 2014 Sep 3;34(36):11929-47. (PMID: 25186741) J Neurosci Res. 1992 Feb;31(2):365-74. (PMID: 1374132) Nat Commun. 2022 Nov 2;13(1):6581. (PMID: 36323693) Elife. 2016 Jun 23;5:. (PMID: 27336724) Immunity. 2019 Mar 19;50(3):764-766. (PMID: 30893590) Immun Ageing. 2022 Jul 25;19(1):34. (PMID: 35879802) Nucleic Acids Res. 2019 Jul 2;47(W1):W199-W205. (PMID: 31114916) Immunology. 2010 Feb;129(2):154-69. (PMID: 20561356) J Neurosci Res. 1991 Feb;28(2):254-60. (PMID: 2033653) BMC Cancer. 2022 Nov 1;22(1):1121. (PMID: 36320006) Mol Cell Biol. 2008 Mar;28(5):1489-502. (PMID: 18180285) Fluids Barriers CNS. 2011 Jan 18;8(1):4. (PMID: 21349152) Nat Immunol. 2017 Feb;18(2):123-131. (PMID: 28092374) Int J Mol Sci. 2020 Mar 13;21(6):. (PMID: 32183047) Trends Cell Biol. 2015 Mar;25(3):171-84. (PMID: 25618329) EMBO Rep. 2015 Apr;16(4):427-46. (PMID: 25722290) J Biol Chem. 2023 Nov;299(11):105322. (PMID: 37805137) Acta Neuropathol. 2016 Sep;132(3):317-38. (PMID: 27522506) Int J Oncol. 2016 Jan;48(1):153-60. (PMID: 26549344) Exp Mol Med. 2020 Sep;52(9):1517-1525. (PMID: 32973221) Trends Immunol. 2012 Dec;33(12):579-89. (PMID: 22926201) Neurol Res. 2008 Oct;30(8):783-93. (PMID: 18826804) Blood. 2011 Jan 27;117(4):e49-56. (PMID: 21084707) Nat Protoc. 2019 Nov;14(11):3059-3081. (PMID: 31586162) Genes Dev. 2008 Mar 15;22(6):734-9. (PMID: 18347092) Nat Commun. 2021 Feb 17;12(1):1088. (PMID: 33597522) IEEE Trans Vis Comput Graph. 2014 Dec;20(12):1983-92. (PMID: 26356912) Cold Spring Harb Perspect Biol. 2015 Jan 05;7(1):a020412. (PMID: 25561720) Science. 2021 Nov 12;374(6569):868-874. (PMID: 34648304) Annu Rev Immunol. 1993;11:767-804. (PMID: 8476577) Front Biosci (Landmark Ed). 2010 Jan 01;15(2):478-536. (PMID: 20036831) Science. 2008 Nov 21;322(5905):1247-50. (PMID: 19023080) Int J Mol Sci. 2022 Nov 04;23(21):. (PMID: 36362301) Immunity. 2019 Apr 16;50(4):955-974. (PMID: 30995509) Nature. 2022 Mar;603(7903):885-892. (PMID: 35165441) Neuron. 2016 Jan 6;89(1):37-53. (PMID: 26687838) Nat Biotechnol. 2018 Dec 03;:. (PMID: 30531897) J Exp Med. 2020 Apr 6;217(4):. (PMID: 32211826) J Clin Invest. 2017 Sep 1;127(9):3210-3219. (PMID: 28862640) Front Immunol. 2022 Feb 22;13:805657. (PMID: 35273596) Front Oncol. 2022 Jun 16;12:920652. (PMID: 35785216) Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):641-6. (PMID: 19129494) Sci Rep. 2023 Jul 24;13(1):11948. (PMID: 37488165) Elife. 2018 Sep 06;7:. (PMID: 30188322) Nat Commun. 2020 Sep 4;11(1):4413. (PMID: 32887883) Cell Syst. 2019 Apr 24;8(4):329-337.e4. (PMID: 30954475) Lancet Neurol. 2015 Apr;14(4):406-19. (PMID: 25792099) J Exp Med. 2019 Nov 4;216(11):2582-2601. (PMID: 31395618) Transl Oncol. 2019 Feb;12(2):236-244. (PMID: 30428404) Cell. 2019 Jun 13;177(7):1888-1902.e21. (PMID: 31178118) Br J Pharmacol. 2011 Oct;164(4):1079-106. (PMID: 21371012) Cell Rep. 2013 Dec 12;5(5):1342-52. (PMID: 24316075) Nature. 2020 Jan;577(7790):399-404. (PMID: 31915375) Immunology. 2018 Jun;154(2):204-219. (PMID: 29513402) Brain Behav Immun. 2020 Oct;89:67-86. (PMID: 32479993) Nat Med. 2013 Dec;19(12):1584-96. (PMID: 24309662) Nat Commun. 2023 May 30;14(1):3106. (PMID: 37253744) Nat Med. 2019 Jun;25(6):988-1000. (PMID: 31086348) Trends Immunol. 2005 Sep;26(9):485-95. (PMID: 16039904) Brain. 2024 Feb 1;147(2):566-589. (PMID: 37776513) Immunity. 2014 Nov 20;41(5):694-707. (PMID: 25517612) Nature. 2019 Jul;571(7764):205-210. (PMID: 31270459) Nat Neurosci. 2012 Jul 26;15(8):1096-101. (PMID: 22837040) BMC Gastroenterol. 2010 Oct 26;10:125. (PMID: 20977743) Front Pharmacol. 2021 Apr 28;12:655052. (PMID: 33995074) J Leukoc Biol. 2011 Apr;89(4):539-56. (PMID: 21169520) Elife. 2019 Aug 20;8:. (PMID: 31429822) Sci Data. 2018 Aug 21;5:180160. (PMID: 30129931) |
| معلومات مُعتمدة: | P30 DK058404 United States DK NIDDK NIH HHS; G20 RR030956 United States RR NCRR NIH HHS; P30 EY008126 United States EY NEI NIH HHS; S10 RR027396 United States RR NCRR NIH HHS; P30 DK020593 United States DK NIDDK NIH HHS; P30 CA068485 United States CA NCI NIH HHS; UL1 RR024975 United States RR NCRR NIH HHS; R21 NS106510 United States NS NINDS NIH HHS |
| تواريخ الأحداث: | Date Created: 20240422 Latest Revision: 20240429 |
| رمز التحديث: | 20240429 |
| مُعرف محوري في PubMed: | PMC11030232 |
| DOI: | 10.1101/2023.02.07.527394 |
| PMID: | 38645082 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.02.07.527394 |
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