MyD88 protein destabilization mitigates NF-κB-dependent protection against macrophage apoptosis

Lainšček, Duško (author), Horvat, Simon (author), Dolinar, Klemen (author), Ivanovski, Filip (author), Romih, Rok (author), Pirkmajer, Sergej (author), Jerala, Roman (author), Manček Keber, Mateja (author)

Various signaling pathways are essential for both the innate immune response and the maintenance of cell homeostasis, requiring coordinated interactions among them. In this study, a mutation in the caspase-1 recognition site within MyD88 abolished inflammasome-dependent negative regulation, causing phenotypic changes in mice with some similarities to human NEMO-deficiencies. The MyD88D162E mutation reduced MyD88 protein levels and colon inflammation in DSS-induced colitis mice but did not affect cytokine expression in bone marrow-derived macrophages (BMDMs). However, compared to MyD88wt counterparts, MyD88D162E BMDMs had increased oxidative stress and dysfunctional mitochondria, along with reduced prosurvival Bcl-xL and BTK expression, rendering cells more prone to apoptosis, exacerbated by ibrutinib treatment. NF-κB activation by lipopolysaccharide mitigated this sensitive phenotype. These findings underscore the importance of MyD88wt signaling for NF-κB activation, protecting against macrophage premature apoptosis at resting state. Targeting MyD88 quantity rather than just its signaling could be a promising strategy for MyD88-driven lymphoma treatment.

• Language: English
• Keywords: MyD88, NF-κB signaling, apoptosis, homeostasis, oxidative stress
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: BF - Biotechnical Faculty; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 14 str.
• Numbering: Vol. 22, art. 549
• PID: 20.500.12556/RUL-165389
• UDC: 577.27
• ISSN on article: 1478-811X
• DOI: 10.1186/s12964-024-01930-1
• COBISS.SI-ID: 215726595
• Publication date in RUL: 05.12.2024

Record is a part of a journal

• Title: Cell communication and signaling
• Shortened title: Cell commun. signal.
• Publisher: BioMed Central
• ISSN: 1478-811X
• COBISS.SI-ID: 513859097

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: imunologija, makrofagi, apoptaza, homeostaza, oksidativni stres, MyD88