Macrophage protease-activated receptor 2 regulates fetal liver erythropoiesis in mice

Abstract

Deficiencies in many coagulation factors and protease-activated receptors (PARs) affect embryonic development. We describe a defect in definitive erythropoiesis in PAR2-deficient mice. Embryonic PAR2 deficiency increases embryonic death associated with variably severe anemia in comparison with PAR2-expressing embryos. PAR2-deficient fetal livers display reduced macrophage densities, erythroblastic island areas, and messenger RNA expression levels of markers for erythropoiesis and macrophages. Coagulation factor synthesis in the liver coincides with expanding fetal liver hematopoiesis during midgestation, and embryonic factor VII (FVII) deficiency impairs liver macrophage development. Cleavage-insensitive PAR2-mutant mice recapitulate the hematopoiesis defect of PAR2-deficient embryos, and macrophage-expressed PAR2 directly supports erythroblastic island function and the differentiation of red blood cells in the fetal liver. Conditional deletion of PAR2 in macrophages impairs erythropoiesis, as well as increases inflammatory stress, as evidenced by upregulation of interferon-regulated hepcidin antimicrobial peptide. In contrast, postnatal macrophage PAR2 deficiency does not have any effect on steady-state Kupffer cells, bone marrow macrophage numbers, or erythropoiesis, but erythropoiesis in macrophages from PAR2-deficient mice is impaired following hemolysis. These data identify a novel function for macrophage PAR2 signaling in adapting to rapid increases in blood demand during gestational development and postnatal erythropoiesis under stress conditions.

Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1–driven fibrotic remodeling in ischemic heart failure

“…Animals and in vivo treatments: 9 to 12 weeks old male mice lacking 21 amino acid of the cytoplasmic tail of TF (TF ΔCT mice) on a C57BL/6J background and PAR2 -/mice on a C57BL/6N background were used along with strain matched controls (26). PAR2 fl/fl mice were crossed to LysMCre mice to generate conditional knockout of PAR2 on myeloid cell compartment (PAR2 fl/fl LysMCre + mice) (15,67), as controls Cre negative PAR2 fl/fl littermates were used. Generation of TF fl/fl LysMCre +/mice has been previously described (68).…”

GPR97 triggers inflammatory processes in human neutrophils via a macromolecular complex upstream of PAR2 activation

“…PAR2 is expressed ubiquitously and its activation has been shown to play multiple immune-regulatory roles including neutrophil activation and inflammatory cytokine production [41][42][43] . Critically, neutrophil activation via the TF/FVIIa/PAR2 axis resulted in trophoblast injury and fetal death in an animal model of autoimmune antiphospholipid syndrome 11 .…”

GPR97-mediated PAR2 transactivation via a mPR3-associated macromolecular complex induces inflammatory activation of human neutrophils

“…5h). PAR2 is expressed ubiquitously and its activation has been shown to play multiple immune-regulatory roles including N activation and inflammatory cytokine production 40,41,42 . Critically, N activation via the TF/FVIIa/PAR2 axis resulted in trophoblast injury and fetal death in an APS animal model 11 .…”