CD47 halts Ptpn6 -deficient neutrophils from provoking lethal inflammation

Abstract

Mice with SHP1 proteins, which have a single amino acid substitution from tyrosine-208 residue to asparagine (hereafter Ptpn6 spin mice), develop an autoinflammatory disease with inflamed footpads. Genetic crosses to study CD47 function in Ptpn6 spin mice bred Ptpn6 spin × Cd47 −/− mice that were not born at the expected Mendelian ratio. Ptpn6 spin bone marrow cells, when transferred into lethally irradiated Cd47 -deficient mice, caused marked weight loss and subsequent death. At a cellular level, Ptpn6 -deficient neutrophils promoted weight loss and death of the lethally irradiated Cd47 −/− recipients. We posited that leakage of gut microbiota promotes morbidity and mortality in Cd47 −/− mice receiving Ptpn6 spin cells. Colonic cell death and gut leakage were substantially increased in the diseased Cd47 −/− mice. Last, IL-1 blockade using anakinra rescued the morbidity and mortality observed in the diseased Cd47 −/− mice. These data together demonstrate a protective role for CD47 in tempering pathogenic neutrophils in the Ptpn6 spin mice.