CD47 halts Ptpn6-deficient neutrophils from provoking lethal inflammation

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.