Novel signaling paradigm regulating TOLL-like receptors in innate immune cells
Bibliographic record
Abstract
T like receptors (TLRs) are essential sensors of microbial attack, and they orchestrate the innate immune response against many microorganisms. The signaling pathways of these mammalian TLRs are well characterized, but the initial molecular mechanisms activated following ligand interactions with their receptors remain poorly defined. Here, we report a novel signaling paradigm initiated by binding of specific TLR ligands (LPS for TLR4, imiquimodfor TLR7, and CpG for TLR9 ) to potentiate G protein-coupled receptor and matrix metalloproteinase-9 (MMP9) activation to induce mammalian Neu1 sialidase. Central to this process is that Neu1-MMP9 complex is bound to TLR-4, -7 and -9 in naive and ligand stimulated macrophage cells as revealed by co-immunoprecipitation and colocalization assays. Using NFκB dependent secreted alkaline phosphatase (SEAP) analysis, ligand-induced TLR activation was significantly inhibited by oseltamivir phosphate (OP), MMP9 inhibitor and BIM23127 (a specific NMBR inhibitor). Mal-2 lectin (Maackiaamurensis agglutinin) binding to immunoprecipitated TLRs in cell lysates from naive but not TLR ligand stimulated RAW-blue macrophage cellsindicated the removal of the α-2,3 sialic acid residues from the stimulated receptor ectodomain. OP, MMP9 inhibitor and BIM-23127 blocked MyD88 recruitment to the ligand stimulated TLR receptors. This study reveals an novel identical GPCR signaling platform to potentiate Neu1 and MMP9 cross-talk on the cell surface and in the endosomal compartments of macrophages that is essential for Toll-like receptor activation, cellular signaling and pro-inflammatory responses. Supported by NSERC to MS and CIHR doctoral award to SA.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".