Abstract
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.
Highlights
The innate immune system is a key player in inflammatory responses to microbial invasion and host cell death
Neutrophil recruitment (NR) to sites of sterile cell injury is more dependent on receptor for advanced glycation end products (RAGE) and IL-1R than toll-like receptors (TLRs) compared to recruitment of monocytes [1]
Investigation of NR in response to tissue injury is critical for understanding inflammation resolution mechanisms and designing pro-resolution therapeutics for non-resolving inflammation
Summary
The innate immune system is a key player in inflammatory responses to microbial invasion and host cell death. Sterile inflammation (SI) is a critical process in the pathogenesis of chronic conditions triggered and sustained by cell death in the absence of exogenous. Endogenous host-derived factors stimulate early neutrophil infiltration at site of injury. Toll-like receptors (TLRs) are unlikely the major sensors of cell death in sterile inflammatory responses. Neutrophil recruitment (NR) to sites of sterile cell injury is more dependent on receptor for advanced glycation end products (RAGE) and IL-1R than TLRs compared to recruitment of monocytes [1]. Tissue hypoxia is a major regulator of NR at sites of SI as extensively described in ischemia-reperfusion injury studies. Extracellular viable mitochondria, released from necrotic cells, generate ATP that triggers the activation of the inflammasome whose role is critical in the initiation of sterile inflammatory response to tissue injury [1]
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