Convergent alteration of granulopoiesis, chemotactic activity, and neutrophil apoptosis during mouse selection for high acute inflammatory response

Neutrophil homeostasis was investi- gated in two mouse lines, AIRmax and AIRmin, genetically selected for high or low acute inflam- matory response (AIR) and compared with uns- elected BALB/c mice. Mature neutrophil pheno- type and functions appeared similar in the three mouse lines. However, an unprecedented pheno- type was revealed in AIRmax animals character- ized by a high neutrophil production in bone mar- row (BM), a high number of neutrophils in blood, a high concentration of chemotactic agents in acryl- amide-induced inflammatory exudates, and an in- creased resistance of locally infiltrated neutrophils to spontaneous apoptosis. In vitro, BM production of neutrophils and eosinophils was accompanied by an unusual high up-regulation of cytokine recep- tors as assessed by antibodies to CD131, which bind the common chain of receptors to interleu- kin (IL)-3, IL-5, and granulocyte macrophage-col- ony stimulating factor. An accelerated neutrophil maturation was also observed in response to all- trans retinoic acid. Several candidate genes can be proposed to explain this phenotype. Yet, more im- portantly, the results underline that genetic selec- tion, based on the degree of AIR and starting from a founding population resulting from the intercross of eight inbred mouse lines, which display a con- tinuous range of inflammatory responses, can lead to the convergent selection of alleles affecting neu- trophil homeostasis. Similar gene combinations may occur in the human with important conse- quences in the susceptibility to inflammatory or infectious diseases and cancer. J. Leukoc. Biol. 74: 497-506; 2003.