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Regulation of chemokine receptor by Toll-like receptor 2 is critical to neutrophil migration and resistance to polymicrobial sepsis
Open accessAbstract
Patients with sepsis have a marked defect in neutrophil migration. Here we identify a key role of Toll-like receptor 2 (TLR2) in the regulation of neutrophil migration and resistance during polymicrobial sepsis. We found that the expression of the chemokine receptor CXCR2 was dramatically down-regulated in circulating neutrophils from WT mice with severe sepsis, which correlates with reduced chemotaxis to CXCL2 in vitro and impaired migration into an infectious focus in vivo. TLR2 deficiency prevented the down-regulation of CXCR2 and failure of neutrophil migration. Moreover, TLR2 −/− mice exhibited higher bacterial clearance, lower serum inflammatory cytokines, and improved survival rate during severe sepsis compared with WT mice. In vitro, the TLR2 agonist lipoteichoic acid (LTA) down-regulated CXCR2 expression and markedly inhibited the neutrophil chemotaxis and actin polymerization induced by CXCL2. Moreover, neutrophils activated ex vivo by LTA and adoptively transferred into naïve WT recipient mice displayed a significantly reduced competence to migrate toward thioglycolate-induced peritonitis. Finally, LTA enhanced the expression of G protein–coupled receptor kinases 2 (GRK2) in neutrophils; increased expression of GRK2 was seen in blood neutrophils from WT mice, but not TLR2 −/− mice, with severe sepsis. Our findings identify an unexpected detrimental role of TLR2 in polymicrobial sepsis and suggest that inhibition of TLR2 signaling may improve survival from sepsis.
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Self-citation
Metadata
- Authors
- Alves-Filho, J. C., Freitas, A., Souto, F. O., Spiller, F., Paula-Neto, H., Silva, J. S., Gazzinelli, R. T., Teixeira, M. M., Ferreira, S. H., & Cunha, F. Q.
- Affiliations
- Department of Pharmacology and
- Universidade do Estado do Rio de Janeiro (BR)
- Department of Immunology, School of Medicine of Ribeirão Preto, University of Säo Paulo, 14049–900 Ribeirão Preto, Brazil;
- Universidade Federal de Minas Gerais (BR)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-10
- Volume
- 106
- Issue
- 10
- Pages
- 4018-4023
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2656197
- OpenAlex
- W2026927834
- Cited by
- 318
- References
- 31
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 11 · 2023: 18 · 2022: 9 · 2021: 11 · 2020: 14 · 2019: 19 · 2018: 8 · 2017: 18 · 2016: 20 · 2015: 12 · 2014: 18 · 2013: 23 · 2012: 24
- FWCI
- 20.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- TLR2, polymicrobial sepsis, neutrophil migration, CXCR2, chemokine receptor down-regulation, lipoteichoic acid, G protein-coupled receptor kinase 2, actin polymerization, bacterial clearance, inflammatory cytokines
- MeSH terms
- Animals, Cell Movement, Chemotaxis, Gene Expression Regulation, Immunity, Innate, Lipopolysaccharides, Neutrophils, Peritonitis, Teichoic Acids, Signal Transduction, Down-Regulation, Survival Analysis, Sepsis, Receptors, Interleukin-8B, Toll-Like Receptor 2, Mice, G-Protein-Coupled Receptor Kinase 2
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