Toll-like receptor-4 genotype influences the survival of cystic fibrosis mice.
Toll-like receptor (Tlr) 4 is a lipopolysaccharide (LPS) receptor that contributes to the regulation of intestinal cell homeostasis, a condition that is altered in the intestines of cystic fibrosis mice. Herein, we assessed whether Tlr4 genotype influences cystic fibrosis intestinal disease by producing and phenotyping 12-wk (adult)- and 4-day (neonate)-old mice derived from BALB cystic fibrosis transmembrane conductance regulator, Cftr(+/tm1Unc) and C.C3-Tlr4(Lps-d)/J (Tlr4(-/-)), progenitors. Intestinal disease was assayed through mouse survival, crypt-villus axis (CVA) length, cell proliferation, bacterial load, bacterial classification, inflammatory cell infiltrate, and mucus content measures. Of the 77 Cftr(-/-) (CF) mice produced, only one Cftr/Tlr4 double-mutant mouse lived to the age of 12 wk while the majority of the remainder succumbed at approximately 4 days of age. The survival of CF Tlr4(+/-) mice exceeded that of both CF Tlr4(+/+) and Cftr/Tlr4 double-mutant mice. Adult CF mice presented increased Tlr4 expression, CVA length, crypt cell proliferation, and bacterial load relative to non-CF mice, but no differences were detected in Tlr4(+/-) compared with Tlr4(+/+) CF mice. The double-mutant neonates did not differ from Tlr4(+/+) or Tlr4(+/-) CF mice by intestinal CVA length or bacterial load, but fewer Tlr4(+/-) CF neonates presented with luminal mucus obstruction in the distal ileum, and the intestinal mast cell increase of CF mice was not evident in double-mutant neonates. We conclude that Tlr4 deficiency reduces the survival, but does not alter the intestinal phenotypes, of extended CVA or increased bacterial load in BALB CF mice.
Canale-Zambrano
Juan C
JC
Dept. of Medicine, McGill Univ., Montreal, Quebec, Canada.
Auger
Meagan L
ML
Haston
Christina K
CK
D000818:Animals; D000831:Animals, Newborn; D015169:Colony Count, Microbial; D003550:Cystic Fibrosis / Q000150:complications* / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D007415:Intestinal Obstruction / Q000209:etiology* / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010641:Phenotype; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D051197:Toll-Like Receptor 4; D019005:Cystic Fibrosis Transmembrane Conductance Regulator