Haney MS, Palovics R, Munson CN, Long C, Johansson PK, Yip O, Dong W, Rawat E, West E, Schlachetzki JCM, et al. APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia. Nature. 2024;628(8006):154–61.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B, Haney MS, Pluvinage JV, Mathur V, Hahn O, Morgens DW, et al. Lipid-droplet-accumulating microglia represent a dysfunctional and Proinflammatory state in the aging brain. Nat Neurosci. 2020;23(2):194–208.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yang D, Wang X, Zhang L, Fang Y, Zheng Q, Liu X, Yu W, Chen S, Ying J, Hua F. Lipid metabolism and storage in neuroglia: role in brain development and neurodegenerative diseases. Cell Biosci. 2022;12(1):106.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yen JJ, Yu II. The role of ApoE-mediated microglial lipid metabolism in brain aging and disease. Immunometabolism (Cobham). 2023;5(1):e00018.

Article  PubMed  Google Scholar 

Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35:441–68.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell. 2017;169(7):1276–e12901217.

Article  CAS  PubMed  Google Scholar 

Deenick EK, Tangye SG. Autoimmunity: IL-21: a new player in Th17-cell differentiation. Immunol Cell Biol. 2007;85(7):503–5.

Article  CAS  PubMed  Google Scholar 

Dolff S, Abdulahad WH, Westra J, Doornbos-van der Meer B, Limburg PC, Kallenberg CG, Bijl M. Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus. Arthritis Res Ther. 2011;13(5):R157.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gharibi T, Hosseini A, Marofi F, Oraei M, Jahandideh S, Abdollahpour-Alitappeh M, Hashemi V, Motallebnezhad M, Babaloo Z, Baradaran B. IL-21 and IL-21-producing T cells are involved in multiple sclerosis severity and progression. Immunol Lett. 2019;216:12–20.

Article  CAS  PubMed  Google Scholar 

Elsaesser H, Sauer K, Brooks DG. IL-21 is required to control chronic viral infection. Science. 2009;324(5934):1569–72.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Frohlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, Weber J, Marsland BJ, Oxenius A, Kopf M. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science. 2009;324(5934):1576–80.

Article  PubMed  Google Scholar 

Ren HM, Kolawole EM, Ren M, Jin G, Netherby-Winslow CS, Wade Q, Shwetank, Rahman ZSM, Evavold BD, Lukacher AE. IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection. Sci Immunol. 2020;5(51).

Agrawal S, Baulch JE, Madan S, Salah S, Cheeks SN, Krattli RP Jr., Subramanian VS, Acharya MM, Agrawal A. Impact of IL-21-associated peripheral and brain crosstalk on the Alzheimer’s disease neuropathology. Cell Mol Life Sci. 2022;79(6):331.

Article  CAS  PubMed  PubMed Central  Google Scholar 

do Sacramento PM, Sales M, Kasahara TM, Monteiro C, Oyamada H, Dias ASO, Lopes L, Castro CT, Rossi AD, Milioni LM, et al. Major depression favors the expansion of Th17-like cells and decrease the proportion of CD39(+)Treg cell subsets in response to Myelin antigen in multiple sclerosis patients. Cell Mol Life Sci. 2022;79(6):298.

Article  PubMed  PubMed Central  Google Scholar 

Clarkson BD, Ling C, Shi Y, Harris MG, Rayasam A, Sun D, Salamat MS, Kuchroo V, Lambris JD, Sandor M, et al. T cell-derived Interleukin (IL)-21 promotes brain injury following stroke in mice. J Exp Med. 2014;211(4):595–604.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Galecka M, Blizniewska-Kowalska K, Orzechowska A, Szemraj J, Maes M, Berk M, Su KP, Galecki P. Inflammatory versus Anti-inflammatory profiles in major depressive Disorders-The role of IL-17, IL-21, IL-23, IL-35 and Foxp3. J Pers Med. 2021;11(2).

Linhares UC, Schiavoni PB, Barros PO, Kasahara TM, Teixeira B, Ferreira TB, Alvarenga R, Hygino J, Vieira MM, Bittencourt VC, et al. The ex vivo production of IL-6 and IL-21 by CD4 + T cells is directly associated with neurological disability in neuromyelitis Optica patients. J Clin Immunol. 2013;33(1):179–89.

Article  CAS  PubMed  Google Scholar 

Rayasam A, Kijak JA, Kissel L, Choi YH, Kim T, Hsu M, Joshi D, Laaker CJ, Cismaru P, Lindstedt A, et al. CXCL13 expressed on inflamed cerebral blood vessels recruit IL-21 producing TFH cells to damage neurons following stroke. J Neuroinflammation. 2022;19(1):125.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Buhrer C, Stahel PF. IL-18: a key player in neuroinflammation and neurodegeneration? Trends Neurosci. 2005;28(9):487–93.

Article  CAS  PubMed  Google Scholar 

Lyra ESNM, Goncalves RA, Pascoal TA, Lima-Filho RAS, Resende EPF, Vieira ELM, Teixeira AL, de Souza LC, Peny JA, Fortuna JTS, et al. Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer’s disease. Transl Psychiatry. 2021;11(1):251.

Article  Google Scholar 

Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF, Sathler LB, Brito-Moreira J, Amaral OB, Silva CA, et al. TNF-alpha mediates PKR-dependent memory impairment and brain IRS-1 Inhibition induced by Alzheimer’s beta-amyloid oligomers in mice and monkeys. Cell Metab. 2013;18(6):831–43.

Article  CAS  PubMed  Google Scholar 

Fraga VG, Magalhaes CA, Loures CMG, de Souza LC, Guimaraes HC, Zauli DAG, Carvalho MDG, Ferreira CN, Caramelli P, de Sousa LP, et al. Inflammatory and Pro-resolving mediators in frontotemporal dementia and Alzheimer’s disease. Neuroscience. 2019;421:123–35.

Article  CAS  PubMed  Google Scholar 

Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med. 2015;3(10):136.

PubMed  PubMed Central  Google Scholar 

Gutierrez IL, Novellino F, Caso JR, Garcia-Bueno B, Leza JC, Madrigal JLM. CCL2 Inhibition of Pro-Resolving mediators potentiates neuroinflammation in astrocytes. Int J Mol Sci. 2022;23(6).

Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, Cheung TH, Zhang B, Fu WY, Liew FY, et al. IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline. Proc Natl Acad Sci U S A. 2016;113(19):E2705–2713.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gao Y, Luo CL, Li LL, Ye GH, Gao C, Wang HC, Huang WW, Wang T, Wang ZF, Ni H, et al. IL-33 provides neuroprotection through suppressing apoptotic, autophagic and NF-kappaB-Mediated inflammatory pathways in a rat model of recurrent neonatal seizure. Front Mol Neurosci. 2017;10:423.

Article  PubMed  PubMed Central  Google Scholar 

Jafarzadeh A, Mahdavi R, Jamali M, Hajghani H, Nemati M, Ebrahimi HA. Increased concentrations of Interleukin-33 in the serum and cerebrospinal fluid of patients with multiple sclerosis. Oman Med J. 2016;31(1):40–5.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu M, Huang J, Liu T, Yuan J, Lv C, Sha Z, Wu C, Jiang W, Liu X, Nie M, et al. Exogenous Interleukin 33 enhances the brain’s lymphatic drainage and toxic protein clearance in acute traumatic brain injury mice. Acta Neuropathol Commun. 2023;11(1):61.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Saresella M, Marventano I, Piancone F, La Rosa F, Galimberti D, Fenoglio C, Scarpini E, Clerici M. IL-33 and its decoy sST2 in patients with Alzheimer’s disease and mild cognitive impairment. J Neuroinflammation. 2020;17(1):174.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Loschinski R, Bottcher M, Stoll A, Bruns H, Mackensen A, Mougiakakos D. IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner. Oncotarget. 2018;9(17):13125–38.

Article  PubMed  PubMed Central