Toll-like receptor-4 genotype influences the survival of cystic fibrosis mice

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2010-08, Vol.299 (2), p.G381-G390
• Main Authors: Canale-Zambrano, Juan C, Auger, Meagan L, Haston, Christina K
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Cells; Colony Count, Microbial; Cystic fibrosis; Cystic Fibrosis - complications; Cystic Fibrosis - microbiology; Cystic Fibrosis - pathology; Cystic Fibrosis - physiopathology; Cystic Fibrosis Transmembrane Conductance Regulator - deficiency; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Gastrointestinal diseases; Genotype; Genotype & phenotype; Haplotypes; Homeostasis; Ileum - metabolism; Ileum - pathology; Intestinal Obstruction - etiology; Intestinal Obstruction - microbiology; Intestinal Obstruction - pathology; Intestinal Obstruction - physiopathology; Kaplan-Meier Estimate; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Mutant Strains; Mutation; Phenotype; Physiology; Rodents; Toll-Like Receptor 4 - deficiency; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism
• ISSN: 0193-1857; 1522-1547; 1522-1547
• DOI: 10.1152/ajpgi.00003.2010

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.