title: Flagellin and LPS each restores rat lymphocyte populations after colorectal irradiation.
abstract: Radiation-induced gastrointestinal toxicity, including its shift of the immune balance, remains a major limitation to delivering tumoricidal doses of abdominal radiation therapy. This study evaluates the effect on the colon's innate and adaptive immune responses to moderate irradiation doses and the therapeutic possibilities of maintaining immune homeostasis. We investigated whether administration of the TLR4 agonist LPS or of the TLR5 agonist flagellin, 3 days after a single 20-Gy colorectal irradiation, modified recruitment of neutrophils, NK cells, or CD4⁺ or CD8⁺ T cells, 7 days postirradiation. Flow cytometric analysis showed that LPS and flagellin reduced irradiation-induced neutrophil infiltration and normalized NK frequency. LPS normalized the CD4⁺ population and enhanced the CD8⁺ population, whereas flagellin maintained the radiation-induced elevation in the frequencies of both. Irradiation also modified TLR4 and TLR5 expression on the surface of both populations, but LPS and flagellin each subsequently normalized them. LPS and flagellin were strong inducers of Th1 cytokines (IL-12p35, IL-12p40, and IFN-γ) and thus, contributed to a shift from the Th2 polarization induced by irradiation toward a Th1 polarization, confirmed by an increase of the T-bet:GATA3 ratio, which assesses the Th1 or Th2 status in mixed cell populations. LPS and flagellin treatment resulted in overexpression of FoxP3, IL-2Rα (CD25), IL-2, and OX40, all expressed specifically and involved in high levels of Treg cell expansion. We observed no variation in Treg function-related expression of IL-10 or CTLA-4. These data suggest that the use of TLR ligands limits the effects of irradiation on innate and adaptive immunity.
authors.affiliation: Laboratory of Radiopathology and Experimental Therapies, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France.
authors.forename: Jean-Victor
authors.initials: JV
authors.lastname: Lacave-Lapalun
authors.affiliation: Laboratory of Radiopathology and Experimental Therapies, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.affiliation: Laboratory of Radiopathology and Experimental Therapies, Institute for Radiological Protection and Nuclear Safety, Fontenay-aux-Roses, France christine.linard@irsn.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Linard
mesh_terms: D000818:Animals; D060833:Cellular Microenvironment; D003106:Colon / Q000276:immunology / Q000528:radiation effects*; D005408:Flagellin / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000032:analysis; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000276:immunology / Q000528:radiation effects*; D018417:Th1 Cells / Q000187:drug effects; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D005408:Flagellin
keywords: TLR ligands; colon; radiation