Modulation function of sphingomyelin molecular species in TLR4 signaling and cell death
Year: 2025
Type: article
Abstract: The innate immune system provides the first line of defense against pathogens. However, the mechanisms underlying its endogenous regulation remain unclear. We identified sphingomyelin (SM) as a novel immunomodulatory ligand. SM in serum consists of various fatty acid species. Our findings reveal that SM species regulate inflammatory cell death and cytokine release in an acyl-chain-dependent manner via Toll-like receptor 4 (TLR4)-myeloid differentiation factor-2 (MD-2) signaling. Specifically, N-lauroyl-D-erythro-sphingosylphosphorylcholine (SM C12) and N-myristoyl-D-erythro-sphingosylphosphorylcholine (SM C14) induce inflammatory cell death and pyroptosis in mouse macrophages. The activation of human caspase-4, mouse caspase-11, and gasdermin D underlies this pyroptotic response, and we have identified SM C12 as a ligand for caspase-4. Our results suggest a dual role for SM in mediating inflammation or suppressing LPS-stimulated inflammation through both cell surface TLR4/MD-2 interaction and intracellular caspase signaling pathways. This newfound understanding of SM's immunomodulatory properties opens avenues for exploring its therapeutic potential in modulating innate immune responses.
Source: Cell Reports
Institutions: Institute for Radiation Sciences, The University of Osaka, The University of Osaka, Institute for Advanced Biosciences, Keio University, Tohoku Medical and Pharmaceutical University, Forefront Research Center, Graduate School of Science, The University of Osaka, Kanazawa Medical University, Tottori University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Naito Foundation, Takeda Science Foundation, Uehara Memorial Foundation, Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Ono Medical Research Foundation, Japan Society for the Promotion of Science, Japan Science and Technology Agency
Awards: G1144211017, 細菌－宿主間ケミカルエコロジー戦略が拓く革新的分子免疫制御, Regulation of innate immune responses through acyl-chain structures of gangliosides, Development of a system to analyze the intracellular dynamics of TLR4 for the discovery of novel vaccine adjuvants, G1880464997, G3297006611, Development of Highly Functionalized Lipid A, G4042395536, イノシトールリン脂質を内因性リガンドとするパイロトーシス機構の新規解明, スフィンゴ糖脂質のアシル鎖構造を介したパイロトーシス制御機序の解明
OpenAlex ID: W4416394263