Pristane-Induced Arthritis Loci Interact with the Slc11a1 Gene to Determine Susceptibility in Mice Selected for High Inflammation

Abstract

AIRmax (maximal inflammation) and AIRmin (minimal inflammation) mice show distinct susceptibilities to pristane-induced arthritis (PIA). The Slc11a1 gene, which regulates macrophage and neutrophil activity, is involved in this infirmity. AIRmaxSS mice homozygous for the non-functional Slc11a1 S (gly169asp) allele obtained by genotype-assisted crosses from AIRmax and AIRmin mice are more susceptible than mice homozygous for the Slc11a1 resistant (R) allele. The present work sought to identify the quantitative trait loci (QTL) regulating PIA and to examine the interactions of these QTL with Slc11a1 alleles in modulating PIA. Mice were given two ip injections of 0.5 mL pristane at 60 day intervals, and the incidence and severity of PIA was scored up to 160 days. Genome-wide linkage studies were performed to search for arthritis QTL in an F2 (AIRmax × AIRmin, n = 290) population. Significant arthritis QTL (LODscore>4) were detected on chromosomes 5 and 8, and suggestive QTL on chromosomes 7, 17 and 19. Global gene expression analyses performed on Affymetrix mouse 1.0 ST bioarrays (27k genes) using RNA from arthritic or control mice paws showed 419 differentially expressed genes between AIRmax and AIRmin mice and demonstrated significantly (P<0.001) over-represented genes related to inflammatory responses and chemotaxis. Up-regulation of the chemokine genes Cxcl1, Cxcl9, Cxcl5, Cxcl13 on chromosome 5 was higher in AIRmaxSS than in the other lines. Macrophage scavenger receptor 1 and hemeoxigenase (decycling) 1 genes on chromosome 8 were also expressed at higher levels in AIRmaxSS mice. Our results show that the gene expression profiles of the two arthritis QTL (on chromosomes 5 and 8) correlate with Slc11a1 alleles, resulting in enhanced AIRmaxSS mice susceptibility to PIA.

The Role of NRAMP1/SLC11A1 Gene Variant D543N (1730G/A) in the Genetic Susceptibility to Develop Rheumatoid Arthritis in the Mexican Mestizo population

“…moreover, it has been reported that the D543n snP apparently confers protection against Mycobacterium tuberculosis reactivation in Cambodian patients infected with HIV (p = 0.04; oR: 0.21) 25 , an association that was not observed in Indian patients 23 . all these data suggest that the D543n SLC11A1 variant has a complex role in the susceptibility to inflammatory and infectious disease, with a relevant interaction with the genetic background of individuals studied 26 .…”

Decreased expression levels of Ifi genes is associated to the increased resistance to spontaneous arthritis disease in mice deficiency of IL-1RA

“…The congenic strain BALB.D1-1 contains a genomic fragment flanked by markers D1Mit55 and D1Mit209 from DBA/1 in BALB/c background [ 20 ]. We first examined the similarities of whole genome gene expression of BALB.D1-1 to the other four strains of mice.…”

“…Because the BALB.D1-1 is deficient in IL-1 receptor antagonist protein (IL-1RA), its expression profile is more similar to the two knockout strains, -/- DBA/1 -/- and BALB/c -/- , than to the wild type strains, BALB/c and DBA/1. Because of the insertion of a fragment from DBA/1, BALB.D1-1 acts similar to -/- DBA/1 -/- , showing resistance to spontaneous arthritis [ 20 ] with a gene expression profile resembling the -/- DBA/1 -/- . However, because BALB.D1-1 is on the BALB/c background, it is least related to DBA/1 with the R value of 0.976964.…”

“…Genomic DNA was extracted from tissues obtained by ear punch. The procedure used has been previously described [ 20 ]. Briefly, DNA was extracted from the tissue and amplification of microsatellite markers conducted by polymerase chain reaction (PCR).…”

Trypanosoma cruziInfection in Genetically Selected Mouse Lines: Genetic Linkage with Quantitative Trait Locus Controlling Antibody Response

“…This gene is also involved in inflammatory autoimmune diseases [72] and seems to interact with other genes to modulate this phenotype [73], as could be the case with T. cruzi infection in mice selected for acute inflammatory reaction.…”