ArticleProceedings of the National Academy of Sciences of the United States of America2012
Conservation and divergence in Toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 190 papers, 5 of them syntheses that pooled it.
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Who cites it
190 citing papers in PubMed, 5 syntheses or guidelines pooled it, 311 citations in OpenAlex.
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- Carbohydrates Metabolic Signatures in Immune Cells: Response to Infection.Frontiers in immunology · 2022Pooled it
- Meta-Analysis ofFrontiers in immunology · 2019Pooled it
- Protection of macrophages from intracellular pathogens by miR-182-5p mimic-a gene expression meta-analysis approach.The FEBS journal · 2018Pooled it
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- Targeting Toll-like Receptor 2: synthetic diacylated lipopeptides polarize equine macrophages towards a pro-inflammatory phenotype.Frontiers in immunology · 2026Article
- The role of immune cells in Hantaan-induced hemorrhagic fever with renal syndrome.Frontiers in immunology · 2026Review
- 3D co-cultures of primary human hepatocytes and Kupffer-like cells to address innate immune responses to rAAV.Scientific reports · 2025Article
- Toll like receptor agonist effects on human CD8+ T cell activation and expression of T cell checkpoint receptors.Human vaccines & immunotherapeutics · 2025Article
- Systems analysis reveals alternate metabolic states adopted bybioRxiv : the preprint server for biology · 2025Article
130 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
25 authors at 9 institutions in 4 countries.
Funding
Abstract
Evolutionary change in gene expression is generally considered to be a major driver of phenotypic differences between species. We investigated innate immune diversification by analyzing interspecies differences in the transcriptional responses of primary human and mouse macrophages to the Toll-like receptor (TLR)-4 agonist lipopolysaccharide (LPS). By using a custom platform permitting cross-species interrogation coupled with deep sequencing of mRNA 5' ends, we identified extensive divergence in LPS-regulated orthologous gene expression between humans and mice (24% of orthologues were identified as "divergently regulated"). We further demonstrate concordant regulation of human-specific LPS target genes in primary pig macrophages. Divergently regulated orthologues were enriched for genes encoding cellular "inputs" such as cell surface receptors (e.g., TLR6, IL-7Rα) and functional "outputs" such as inflammatory cytokines/chemokines (e.g., CCL20, CXCL13). Conversely, intracellular signaling components linking inputs to outputs were typically concordantly regulated. Functional consequences of divergent gene regulation were confirmed by showing LPS pretreatment boosts subsequent TLR6 responses in mouse but not human macrophages, in keeping with mouse-specific TLR6 induction. Divergently regulated genes were associated with a large dynamic range of gene expression, and specific promoter architectural features (TATA box enrichment, CpG island depletion). Surprisingly, regulatory divergence was also associated with enhanced interspecies promoter conservation. Thus, the genes controlled by complex, highly conserved promoters that facilitate dynamic regulation are also the most susceptible to evolutionary change.
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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.