Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

Abstract

Mice selected for the maximum acute inflammatory reaction (AIRmax) are highly susceptible to pristane-induced arthritis (PIA), whereas mice selected for the minimum response (AIRmin) are resistant. These lines show distinct patterns of leukocyte infiltration and R and S allele frequency disequilibrium of the solute carrier family 11a member 1 (Slc11a1) gene. In order to study the interactions of the Slc11a1 R and S alleles with the inflammation modulating Quantitative Trait Loci (QTL) during PIA development, homozygous AIRmax RR , AIRmax SS , AIRmin RR and AIRmin SS lines were produced by genotype-assisted breedings. These mice received two intraperitoneal injections of 0.5 ml pristane at 60-day intervals, and the subsequent development of arthritis was assessed for 210 days. Cytokine-secreting cell profiles were investigated using enzyme-linked immunospot. Arthritis incidence in AIRmax RR mice reached 29%, whereas PIA incidence in AIRmax SS mice was 70% by day 180. AIRmin RR mice were resistant, whereas 13.3% of AIRmin SS mice became arthritic. The presence of the defective S allele also increased arthritis severity, although acute inflammation was higher in mice bearing the R allele. A predominant Th0/Th2-type response in Slc11a1 SS mice was observed. These results indicate that Slc11a1 is a strong candidate for the QTL modulating acute inflammation and for PIA.

Periodontitis and arthritis interaction in mice involves a shared hyper-inflammatory genotype and functional immunological interferences

“…[4][5][6][7] Accordingly, our data show that AIRmin and AIRmax mice strains share the susceptibility/resistance phenotype to both PIA and ePD. [24][25][26][27][28] This finding is reinforced in the view of the absence of environmental factors potentially involved in such interaction (namely socio-economic status and tobacco smoking) 16 in the experimental models used in this study. Nevertheless, noncausal theory is supported by studies that independently implicated specific polymorphisms and human leukocyte antigen molecules as susceptibility factors for both RA and PD.…”

“…Indeed, RA can increase the incidence and severity of PD (independently or only partially dependent) of oral hygiene status or modifying factors. [4][5][6][7]15,16,35 Accordingly, our results show that PIA increase the severity of ePD in AIRmax mice strain, whereas in AIRmin strain (resistant to PIA development), [25][26][27][28] the severity of ePD was not altered by pristane injection, showing that the development of PIA, and not the pristane injection, is involved in the modulation of ePD severity. Similarly, adjuvant-induced arthritis in rats also results in signs of periodontal destruction.…”

“…1 Although the exact SNPs underlying such differential responsiveness are under investigation, one genetic variation involved in the control of immune inflammatory reactions between AIRmin and AIRmax strains is well known and involves the gene SLC11A1 (NRAMP1). 28,37 Interestingly, SNPs in SLC11A1 have been associated with the resistance/ susceptibility to human RA development, [38][39][40] but unfortunately no data regarding SLC11A1 association with human PD is available in the literature. Accordingly, with the shared genetic susceptibility hypothesis, preliminary data from our group 41 point to a significant higher frequency of the 3/3 genotype of SLC11A1 rs34448891 SNP (earlier associated to RA) 38 in chronic PD patients.…”

“…15,16 Experimental studies reinforce the noncausal shared genetic susceptibility hypothesis as mouse lines phenotype selected for the acute inflammatory reactivity maximum (AIRmax) or minimal (AIRmin) share the susceptibility or resistance phenotype to both chronic models of pristane-induced arthritis (PIA) and Actinobacillus actinomycetemcomitansinduced PD. [24][25][26][27][28] AIRmax and AIRmin mice were developed through bidirectional genetic selection, starting from a highly polymorphic population (F0) derived from the intercrossing of eight inbred mouse strains (A, DBA2, P, SWR, CBA, SJL, BALB/c, and C57BL/6), and the progressive divergence of the AIRmax and AIRmin lines during successive generations of selective breeding reached 20-and 2.5-fold differences in leukocyte infiltration and exudated protein concentrations, respectively. 27 These differences resulted from the accumulation of alleles endowed with opposite and additive effects on the inflammatory response.…”

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

“…nRamP1 is expressed by monocytes, macrophages, and polymorphonuclear neutrophils, and has an important role in the control of replication of intracellular parasites by altering the intravacuolar environment of the microbe-containing phagolysosome 4,5 . In addition, nRamP1 seems to be involved in the priming and activation of phagocytes, participating in the induction of synthesis of proinflammatory cytokines (tumor necrosis factor-a, interleukin-1) and nitric oxide as well as in the expression of class II major histocompatibility complex (mHC) molecules [5][6][7][8] . therefore, it is very feasible that nRamP1 may have a relevant role in the pathogenesis of inflammatory and autoimmune diseases.…”