Quantitative Trait Loci and Candidate Genes for Neutrophil Recruitment in Sterile Inflammation Mapped in AXB-BXA Recombinant Inbred Mice.
Neutrophil recruitment (NR) to sites of sterile inflammation plays a key role in tissue damage and healing potential of lesions characteristic to non-infectious inflammatory diseases. Previous studies suggested significant genetic control of neutrophil survival, function, and migration in inflammatory responses to endogenous and exogenous stimuli. We have mapped the murine genome for quantitative trait loci (QTLs) harbouring genetic determinants that regulate NR in SI using a murine model of chemically-induced peritonitis. NR was quantified in 16 AXB-BXA recombinant inbred strains and their progenitors, A/J (A) and C57BL/6J (B). A continuous distribution of NR was found among the strains, with parent B showing higher NR and parent A showing lower NR (3.0-fold difference, p=0.05). Within the progeny strains, a 5.5-fold difference in NR was observed between the lowest, BXA1, and the highest responders AXB19 (p<0.001). This data was analyzed using GeneNetwork, which linked NR to one significant QTL on chromosome 12 (Peritoneal Neutrophil Recruitment 1, PNR1) and two suggestive QTLs (PNR2, PNR3) on chromosomes 12 and 16 respectively. Sixty-four candidate genes within PNR1 were cross-referenced with currently published data, mRNA expression from two NR microarrays, and single nucleotide polymorphism analysis. The present study brings new light into the genetics of NR in response to cell injury and highlights potential candidate genes Hif1α, Fntb, and Prkch and their products for further studies on neutrophil infiltration and inflammation resolution in sterile inflammation.
Department of Periodontology, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
Quyen
Q
Cheng
Centre for the Study of Pain, Faculties of Dentistry and Medicine, University of Toronto, Toronto, Ontario, Canada.
Ze'ev
Z
Seltzer
Department of Periodontology, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
Corneliu
C
Sima
Department of Periodontology, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
Flavia S
FS
Lakschevitz
Department of Periodontology, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada; Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
Michael
M
Glogauer
D000818:Animals; D002874:Chromosome Mapping; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005838:Genotype; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020556:Neutrophil Infiltration / Q000235:genetics*; D010538:Peritonitis / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci