Reduced bone marrow adrenergic receptor signaling modulates PVN inflammatory factors

INTRODUCTION Neurogenic hypertension is characterized by neuroinflammation and increased sympathetic nerve activity (SNA) to the periphery, including the bone marrow (BM). The BM SNA governs diurnal regulation of the BM hematopoietic cell turnover, with inflammatory cells typically released during the active period. We have previously shown that chronic increase in the BM SNA leads to elevation of inflammatory factors and release of inflammatory cells in angiotensin II (Ang II) hypertension (HTN). Moreover, extravasation of the BM‐derived inflammatory cells to the brain cardioregulatory regions, including the paraventricular nucleus (PVN), contributes to neuroinflammation and thus the pathophysiology of HTN. Therefore, we hypothesize that reduction in the effects of SNA on BM inflammatory cells will result in suppression of the inflammatory profiles in BM and PVN. METHODS A novel chimeric BM mouse was created by reconstituting sub lethally‐ irradiated C57BL/6J mice with whole BM cells from adrenergic beta 1 and beta 2 receptor knock out (AdrB1.B2KO) mice (Jax Labs). Following recovery, relative expression levels of Adrb1 in circulating mononuclear cells were assessed using quantitative RT PCR, in order to confirm the success of irradiation/reconstitution. Total RNA from PVN and BM was isolated and purified, and gene expression profiles were determined using a mouse 60K Agilent array. Differentially expressed gene networks were determined in each tissue using Pathway Studio (Elsevier). RESULTS There were 8563 and 477 differentially expressed probes in the BM and PVN of AdrB1.B2 KO mice, respectively (FDR <0.05). Upon further investigation into the 53 gene networks differentially expressed in the BM and PVN in the AdrB1.B2 KO mice compared to CNT, it was determined that 13 pathways were related to the immune system. In the BM alone, 41 gene networks associated to immunity were observed in the KO chimera vs CNT (p <0.05). This included a decrease in gene network that included T cell adhesion and leukocyte accumulation gene networks (P<0.05). In terms of specific transcripts associated with these networks, CD4 and CD8a expression was downregulated by 1.3 fold (p<0.007), and 2.6 fold (p<0.01) respectively. In the PVN, there was a 1.3 fold downregulation of IL17 receptor alpha and beta (p<0.015), as well as a decrease in CCL2 expression (p<0.018). CONCLUSION In summary, reduction in responsiveness of the BM hematopoietic cells to SNA is associated with a reduction of inflammatory mediators in both the BM and PVN. Therefore, BM cells’ ability to respond to SNA stimulation can affect both central and peripheral inflammatory responses. This is expected to have significant implication in neurogenic HTN, characterized by both increased sympathetic drive and exaggerated immune responses.