STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ.

Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFR alpha and PDGFR beta. Gain-of-function mutations in human PDGFRB have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether PDGFRB mutations alone are responsible. Mice with constitutive PDGFR beta signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammation. Here we used a genetic approach to investigate the mechanism of autoinflammation in Pdgfrb(+/D849V) mice and test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this phenotype. We show that Pdgfrb(+/D849V) mice with Stat1 knockout (Stat1(-/-) Pdgfrb(+/D849V)) are rescued from autoinflammation and have improved life span compared with Stat1(+/-) Pdgfrb(+/D849V) mice. Furthermore, PDGFR beta-STAT1 signaling suppresses PDGFR beta itself. Thus, Stat1(-/-) Pdgfrb(+/D849V) fibroblasts exhibit increased PDGFR beta signaling, and mice develop progressive overgrowth, a distinct phenotype from the wasting seen in Stat1(+/-) Pdgfrb(+/D849V) mice. Deletion of interferon receptors (Ifnar1 or Ifngr1) does not rescue wasting in Pdgfrb(+/D849V) mice, indicating that interferons are not required for autoinflammation. These results provide functional evidence that elevated PDGFR beta signaling causes tissue wasting or overgrowth reminiscent of human genetic syndromes and that the STAT1 pathway is a crucial modulator of this phenotypic spectrum.