Cell-intrinsic complement C3 suppresses IFN-β production in macrophages
- 1Norwegian University of Science and Technology
Abstract
The cell-intrinsic complement system has emerged as an important orchestrator of a variety of cell-physiological processes, with complement components interacting with intracellular effector systems to regulate cellular responses to pathogens or noxious stimuli. For instance, intracellular C5 signaling through a mitochondrial C5a receptor (C5aR1) controls IL-1{beta} production in human monocytes and macrophages. Here, we investigated whether cell-intrinsic C3 similarly regulates inflammatory responses in macrophages. In LPS-stimulated C3 knockout THP-1-derived macrophages, interferon (IFN)-{beta} production was increased, accompanied by elevated expression of interferon-stimulated genes and enhanced secretion of IFN-induced cytokines and chemokines. C3-deficient cells showed increased phosphorylation of IRF3 at Ser396 and a stabilization of the interaction between IRF3 and TBK1, along with enhanced IRF3 dimerization and nuclear translocation. TBK1 phosphorylation was unaffected, indicating that C3 limits IRF3-TBK1 complex formation rather than upstream TBK1 activation. Small-molecule inhibitors of complement factors B and D restored full-length C3 abundance in LPS-stimulated primary human macrophages, consistent with inhibition of the C3 convertase. It also reduced LPS-induced IFN-{beta} production in primary human macrophages and THP-1 cells, suggesting that full-length, uncleaved C3 suppresses IFN-{beta} production. Collectively, these findings identify cell-intrinsic C3 as a suppressor of IFN-{beta} production in human macrophages, highlighting the importance of the cell-intrinsic complement system in fine-tuning inflammatory responses to pathogens.
Related
- Dendrimer Delivered shRNA Targeting the CCL20-CCR6 Axis Suppresses Complement-Mediated Microglial Synaptic Pruning and Ameliorates Chronic Neuroinflammation After Repetitive Traumatic Brain Injury
- Tumor-intrinsic PTPN12 suppresses anti-tumor immunity in colorectal cancer by restraining a dual epigenetic and cytoskeletal dsRNA sensing program
- Activation of KCa3.1 K⁺ Channel Suppresses COX2- and ARG1-Dependent Immunosuppressive Metabolic Programs in THP-1-Derived M₂-like Macrophages.
- Decanoic acid additively suppresses IL-1β and enables pharmacologic dexamethasone dose-sparing in LPS/ATP-stimulated THP-1 macrophages
- Targeting the Complement C1 Proteases Using Camelid-Derived Single Domain Antibodies: Production, Characterization and Possible Application for Tissue/Fluid Analysis.
BibTeX
@misc{kristensen2026cellintrinsic,
title = {{Cell-intrinsic complement C3 suppresses IFN-β production in macrophages}},
author = {S. Kristensen and C. Arseth and M. Yurchenko and L. Ryan and I. Fjellvaer and K. Rasheed and S. Ullmann and C. Kemper and H. Husebye and T. Espevik and T. H. Flo},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.26.746684},
url = {https://www.biorxiv.org/content/10.64898/2026.08.26.746684v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cell-intrinsic complement C3 suppresses IFN-β production in macrophages
AU - S. Kristensen
AU - C. Arseth
AU - M. Yurchenko
AU - L. Ryan
AU - I. Fjellvaer
AU - K. Rasheed
AU - S. Ullmann
AU - C. Kemper
AU - H. Husebye
AU - T. Espevik
AU - T. H. Flo
PY - 2026
DA - 2026/08/26
PB - bioRxiv
DO - 10.64898/2026.08.26.746684
UR - https://www.biorxiv.org/content/10.64898/2026.08.26.746684v1
AB - The cell-intrinsic complement system has emerged as an important orchestrator of a variety of cell-physiological processes, with complement components interacting with intracellular effector systems to regulate cellular responses to pathogens or noxious stimuli. For instance, intracellular C5 signaling through a mitochondrial C5a receptor (C5aR1) controls IL-1{beta} production in human monocytes and macrophages. Here, we investigated whether cell-intrinsic C3 similarly regulates inflammatory responses in macrophages. In LPS-stimulated C3 knockout THP-1-derived macrophages, interferon (IFN)-{beta} production was increased, accompanied by elevated expression of interferon-stimulated genes and enhanced secretion of IFN-induced cytokines and chemokines. C3-deficient cells showed increased phosphorylation of IRF3 at Ser396 and a stabilization of the interaction between IRF3 and TBK1, along with enhanced IRF3 dimerization and nuclear translocation. TBK1 phosphorylation was unaffected, indicating that C3 limits IRF3-TBK1 complex formation rather than upstream TBK1 activation. Small-molecule inhibitors of complement factors B and D restored full-length C3 abundance in LPS-stimulated primary human macrophages, consistent with inhibition of the C3 convertase. It also reduced LPS-induced IFN-{beta} production in primary human macrophages and THP-1 cells, suggesting that full-length, uncleaved C3 suppresses IFN-{beta} production. Collectively, these findings identify cell-intrinsic C3 as a suppressor of IFN-{beta} production in human macrophages, highlighting the importance of the cell-intrinsic complement system in fine-tuning inflammatory responses to pathogens.
ER -