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