ArticleScience signaling2016
Comprehensive RNAi-based screening of human and mouse TLR pathways identifies species-specific preferences in signaling protein use.
Article in Science signaling, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
55 citing papers in PubMed, 80 citations in OpenAlex.
- IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: a phase 1 trial.Nature medicine · 2023Trial
- The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.Arthritis & rheumatology (Hoboken, N.J.) · 2021Trial
- Quantitative Modeling of TLR Signaling Reveals Missing Negative Feedback Guiding Identification of TANK-IKKε Checkpoint.bioRxiv : the preprint server for biology · 2026Article
- Regulatory interplay between nitric oxide and heme in redox signaling and inflammation.Redox biology · 2026Review
- The role of immune cells in Hantaan-induced hemorrhagic fever with renal syndrome.Frontiers in immunology · 2026Review
- Article
- Turning Susceptibility into Strength: A New Era of Durable Resistance in Plants Through Genome Editing.Plants (Basel, Switzerland) · 2025Review
- Regulation of Neuroinflammation by Microglial DUBA-IRAK1-IKKβ Signaling Loop.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- IRAK signaling in cancers: mechanisms, targeting, and clinical implications.Expert opinion on investigational drugs · 2025Review
- IRAK4 Targeting: A Breakthrough Approach to Combat Hidradenitis Suppurativa.Biologics : targets & therapy · 2025Review
- A Chimeric Peptide Derived from a Bacterial Effector Protein Attenuates TLR-2/4-Mediated Production of Pro-Inflammatory Cytokines and Enhances the Cellular Availability of Gentamicin.Journal of inflammation research · 2025Article
- Enhancing vaccine effectiveness in the elderly to counter antibiotic resistance: The potential of adjuvants via pattern recognition receptors.Human vaccines & immunotherapeutics · 2024Review
- Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases.Journal of medicinal chemistry · 2024Article
- Recent Advances in IRAK1: Pharmacological and Therapeutic Aspects.Molecules (Basel, Switzerland) · 2024Review
- Gestation-dependent increase in cervicovaginal pro-inflammatory cytokines and cervical extracellular matrix proteins is associated with spontaneous preterm delivery within 2 weeks of index assessment in South African women.Frontiers in immunology · 2024Article
- Brain organoids engineered to give rise to glia and neural networks after 90 days in culture exhibit human-specific proteoforms.Frontiers in cellular neuroscience · 2024Article
- hcHCR: High-Throughput Single-Cell Imaging of RNA in Human Primary Immune Cells.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Single-cell analysis reveals a weak macrophage subpopulation response to Mycobacterium tuberculosis infection.Cell reports · 2023Article
- Comprehensive immunoprofiling and systematic adjuvant comparisons for identifying suitable vaccine: Adjuvant pairings.Human vaccines & immunotherapeutics · 2023Article
- Regulation of innate immune signaling by IRAK proteins.Frontiers in immunology · 2023Review
Corrections and comments
- Commented on by
Authors and funding
15 authors at 5 institutions in 3 countries.
Funding
Abstract
Toll-like receptors (TLRs) are a major class of pattern recognition receptors, which mediate the responses of innate immune cells to microbial stimuli. To systematically determine the roles of proteins in canonical TLR signaling pathways, we conducted an RNA interference (RNAi)-based screen in human and mouse macrophages. We observed a pattern of conserved signaling module dependencies across species, but found notable species-specific requirements at the level of individual proteins. Among these, we identified unexpected differences in the involvement of members of the interleukin-1 receptor-associated kinase (IRAK) family between the human and mouse TLR pathways. Whereas TLR signaling in mouse macrophages depended primarily on IRAK4 and IRAK2, with little or no role for IRAK1, TLR signaling and proinflammatory cytokine production in human macrophages depended on IRAK1, with knockdown of IRAK4 or IRAK2 having less of an effect. Consistent with species-specific roles for these kinases, IRAK4 orthologs failed to rescue signaling in IRAK4-deficient macrophages from the other species, and only mouse macrophages required the kinase activity of IRAK4 to mediate TLR responses. The identification of a critical role for IRAK1 in TLR signaling in humans could potentially explain the association of IRAK1 with several autoimmune diseases. Furthermore, this study demonstrated how systematic screening can be used to identify important characteristics of innate immune responses across species, which could optimize therapeutic targeting to manipulate human TLR-dependent outputs.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.