Journal
NATURE MEDICINE
Volume 8, Issue 11, Pages 1296-1302Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm786
Keywords
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Funding
- Arthritis Research UK [15755] Funding Source: Medline
- NIDCR NIH HHS [P01 DE013499, P01-DE13499] Funding Source: Medline
- NIGMS NIH HHS [R01 GM038765, R37 GM038765, GM38765] Funding Source: Medline
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Aspirin (ASA) and dexamethasone (DEX) are widely used anti-inflammatory agents yet their mechanism(s) for blocking polymorphonuclear neutrophil (PMN) accumulation at sites of inflammation remains unclear. Here, we report that inhibition of PMN infiltration by ASA and DEX is a property shared by aspirin-triggered lipoxins (ATL) and the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides that are both generated in vivo and act at the lipoxin A(4) receptor (ALXR/FPRL1) to halt PMN diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of PMN receptors. In addition, the combination of both ATL and ANXA1-derived peptides limited PMN infiltration and reduced production of inflammatory mediators (that is, prostaglandins and chemokines) in vivo. Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci.
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