title: Flagellin or lipopolysaccharide treatment modified macrophage populations after colorectal radiation of rats.
abstract: Radiation-induced acute intestinal toxicity remains a major limitation to the delivery of tumoricidal doses of colorectal irradiation. Recent reports indicate that Toll-like receptor (TLR) agonists TLR4 and TLR5 protect against toxicity due to intestinal irradiation. The phenotype (M1 or M2) of macrophages expressing TLRs may play a role in tissue repair. The aim was to investigate whether administration of TLR4 agonist lipopolysaccharide (LPS) or TLR5 agonist flagellin after irradiation modified the recruitment and phenotype of colonic macrophages and improved tissue damage. Rats were exposed to single 20- or 27-Gy doses of colorectal irradiation. TLR4 agonist LPS or TLR5 agonist flagellin (at 50 or 200 µg/rat) was administered i.p. 3 days after irradiation. Flow cytometric analysis, immunostaining, and real-time polymerase chain reaction analysis were used to assess the M1/M2 phenotype and crypt cell proliferation 7 days after irradiation. Irradiation (20 and 27 Gy) increased TLR4⁺ and TLR5⁺ macrophage frequency in the mucosa. LPS or flagellin administration maintained this elevated frequency after the 27-Gy irradiation. LPS and flagellin drove macrophages toward the anti-inflammatory M2 phenotype by increasing Arg1 and CD163 expression and microenvironmental effector molecules (C-C motif chemokine 22, transforming growth factor-β1, and interleukin-10). Proliferating cell nuclear antigen immunostaining, Ki67 expression, and antimicrobial factor Reg3γ showed that the M2 shift correlated with epithelial regeneration. In conclusion, administration of either LPS or flagellin after colorectal irradiation may provide effective protection against epithelial remodeling. This tissue repair was associated with an M2 macrophage shift. Using TLR agonists to moderately activate innate immunity should be considered as a strategy for protecting healthy tissue from irradiation.
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: Lacavé-Lapalun
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.forename: Christine
authors.initials: C
authors.lastname: Linard
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003106:Colon / Q000187:drug effects* / Q000276:immunology / Q000502:physiology / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000276:immunology / Q000532:radiotherapy; D004307:Dose-Response Relationship, Radiation; D005408:Flagellin / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000502:physiology / Q000528:radiation effects; D008024:Ligands; D008070:Lipopolysaccharides / Q000627:therapeutic use; D008262:Macrophage Activation / Q000187:drug effects / Q000528:radiation effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D058990:Molecular Targeted Therapy; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000187:drug effects / Q000276:immunology / Q000502:physiology / Q000528:radiation effects; D012038:Regeneration / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000819:agonists* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008024:Ligands; D008070:Lipopolysaccharides; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; C440499:lipopolysaccharide, Escherichia coli O111 B4; D005408:Flagellin