Protective roles of CX3CR1-mediated signals in toxin A-induced enteritis through the induction of heme oxygenase-1 expression.
The injection of Clostridium difficile toxin A into the ileal loops caused fluid accumulation with the destruction of intestinal epithelial structure and the recruitment of neutrophils and macrophages. Concomitantly, intraileal gene expression of CX3CL1/fractalkine (FKN) and its receptor, CX3CR1, was enhanced. When treated with toxin A in a similar manner, CX3CR1-deficient (CX3CR1(-/-)) mice exhibited exaggerated fluid accumulation, histopathological alterations, and neutrophil recruitment, but not macrophage infiltration. Mice reconstituted with CX3CR1(-/-) mouse-derived bone marrow cells exhibited exacerbated toxin A-induced enteritis, indicating that the lack of the CX3CR1 gene for hematopoietic cells aggravated toxin A-induced enteritis. A heme oxygenase-1 (HO-1) inhibitor, tin-protoporphyrin-IX, markedly increased fluid accumulation in toxin A-treated wild-type mice, indicating the protective roles of HO-1 in this situation. HO-1 expression was detected mainly in F4/80-positive cells expressing CX3CR1, and CX3CR1(-/-) mice failed to increase HO-1 expression after toxin A treatment. Moreover, CX3CL1/FKN induced HO-1 gene expression by isolated lamina propria-derived macrophages or a mouse macrophage cell line, RAW264.7, through the activation of the ERK signal pathway. Thus, CX3CL1/FKN could induce CX3CR1-expressing macrophages to express HO-1, thereby ameliorating toxin A-induced enteritis.
Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
Masanori
M
Inui
Yuko
Y
Ishida
Akihiko
A
Kimura
Yumi
Y
Kuninaka
Naofumi
N
Mukaida
Toshikazu
T
Kondo
D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D054428:Chemokine CX3CL1 / Q000096:biosynthesis / Q000235:genetics; D016360:Clostridioides difficile / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004751:Enteritis / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control*; D004768:Enterotoxins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D001427:Bacterial Toxins; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D004768:Enterotoxins; D019707:Receptors, Chemokine; C041348:tcdA protein, Clostridium difficile; D051547:Heme Oxygenase-1; D048049:Extracellular Signal-Regulated MAP Kinases