Abstract Body: AngiotensinII (AngII) infusion induces the release of Placental Growth Factor (PlGF) in the spleen after sympathetic discharge and promotes T cells egression and infiltration in target organs of hypertension (PMID: 25517614). Here we explore the role of Neuropilin-1 (NRP1) as PlGF receptor expressed on precursors of Dendritic cells (DCs), in priming the splenic immune response in hypertension. We used flow cytometry, immunohistochemistry and tail cuff plethysmography to evaluate the involvement of PlGF-NRP1 pathway in neuroimmune activation of splenic immune response in hypertension.
We found that AngII increases the expression of NRP1 in monocyte-derived DCs (MoDCs). To explore the involvement of the splenic sympathetic nervous system (SNS) in the regulation of this response, we subjected mice to SNS denervation by celiac ganglionectomy (CGX) finding that CGX hampered NRP1 upregulation after AngII. To evaluate the role of NRP1 in transducing PlGF effect in priming immune response, we assessed an in vitro standard differentiation protocol of monocytes in DCs. We observed that CD86 and MHCII expressions were upregulated in MoDCs from the spleen of WT mice cultured in the standard medium plus recombinant PlGF (rPlGF). On the contrary, CD86 and MHCII were similarly expressed on MoDCs from mice with a selective deletion of NRP1 in myeloid lineage (NRP1^myeKO) cultured with and without rPlGF. To confirm the involvement of NRP1 in immune response in vivo and in blood pressure (BP) regulation, we infused NRP1^myeKO mice with AngII finding that they were protected from BP increase. The deletion of NRP1 hampered the maturation of splenic MoDCs and the expression of co-stimulation molecules. In addition, NRP1^myeKO AngII mice were protected from T cells egression from the spleen and infiltration in target organs of hypertension.
PlGF-NRP1 pathway is a key mechanism that initiates the immune response involved in hypertension: PlGF is activated in the spleen through a neuroimmune mechanism by hypertensive stimuli and promotes the maturation of MoDCs through its receptor NRP1; activated MoDCs primes T cells in the spleen which move toward target organs where they affect blood pressure.