Brain-Derived Neurotrophic Factor Deficiency Exacerbates Innate Immune Responses by Enhancing NLRP3 Inflammasome Activation and GSDMD-Mediated Pyroptosis in Mice

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dc.contributor.authorErdem, Seniz
dc.contributor.authorSaglam, Neslihan
dc.contributor.authorSahin, Elif
dc.contributor.authorErdem, Mehmet
dc.contributor.authorAbidin, Ismail
dc.contributor.authorAlver, Ahmet
dc.date.accessioned2026-06-19T06:37:41Z
dc.date.available2026-06-19T06:37:41Z
dc.date.issued2026
dc.departmentMalatya Turgut Özal Üniversitesi
dc.description.abstractBackground and Objectives: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a key innate immune complex, and its aberrant activation contributes to metabolic and neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with anti-inflammatory and metabolic regulatory functions, but its role in NLRP3 inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis remains unclear. The aim of this study was to investigate the effects of BDNF deficiency on LPS- and nigericin-induced NLRP3 inflammasome activation and GSDMD-mediated pyroptosis in vivo, and to elucidate the involvement of NF-kappa B signaling, autophagy, and ESCRT-III-dependent plasma membrane repair in this process. Materials and Methods: In this in vivo study, male Bdnf +/+ and Bdnf +/- mice were subjected to lipopolysaccharide (LPS) plus nigericin-induced NLRP3 inflammasome activation. Serum and hippocampus, cortex, liver, epididymal adipose, and muscle tissues were collected 24 h after stimulation for analysis of inflammasome-related, autophagy-related, and membrane repair-related proteins by Western blotting and of serum BDNF, interleukin-1 beta (IL-1 beta), and interleukin-18 (IL-18) by ELISA. Results: Bdnf +/- mice displayed significantly reduced circulating BDNF levels and exhibited exaggerated LPS plus nigericin-induced increases in IL-1 beta and IL-18 compared with Bdnf +/+ mice. Across all tissues, BDNF deficiency enhanced NF-kappa B p65, NLRP3, active caspase-1 p20, and GSDMD expression, indicating amplified inflammasome activation and pyroptosis. Conversely, LC3B and SQSTM1/p62 levels were decreased, and VPS4A expression, a key component of the ESCRT-III membrane repair machinery, was suppressed in Bdnf +/- mice, suggesting impaired selective autophagy, autophagosome formation, and plasma membrane repair. Conclusions: Together, these findings indicate that BDNF restrains NLRP3 inflammasome activation and GSDMD-mediated pyroptosis through inhibition of NF-kappa B signaling and coordinated activation of autophagy and ESCRT-III-dependent membrane repair. BDNF thus emerges as an endogenous negative regulator of inflammasome activity and a potential therapeutic target for conditions characterized by aberrant NLRP3-driven inflammation.
dc.description.sponsorshipScientific Research Projects Coordination Unit of Karadeniz Technical University [TDK-2021-9686, TSA-2023-10700]
dc.description.sponsorshipThis research was funded by Scientific Research Projects Coordination Unit of Karadeniz Technical University, Turkey, grant numbers TDK-2021-9686 and TSA-2023-10700.
dc.identifier.doi10.3390/medicina62020384
dc.identifier.issn1010-660X
dc.identifier.issn1648-9144
dc.identifier.issue2
dc.identifier.pmid41752782
dc.identifier.scopus2-s2.0-105031234276
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.3390/medicina62020384
dc.identifier.urihttps://hdl.handle.net/20.500.12899/5167
dc.identifier.volume62
dc.identifier.wosWOS:001700760200001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherMdpi
dc.relation.ispartofMedicina-Lithuania
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_WOS_20260612
dc.subjectBdnf
dc.subjectEscrt-Iii Machinery
dc.subjectNlrp3 Inflammasome
dc.subjectPyroptosis
dc.subjectSelective Autophagy
dc.titleBrain-Derived Neurotrophic Factor Deficiency Exacerbates Innate Immune Responses by Enhancing NLRP3 Inflammasome Activation and GSDMD-Mediated Pyroptosis in Mice
dc.typeArticle

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