Myeloid-Specific JAK2 Contributes to Inflammation and Salt Sensitivity of Blood Pressure, 2024, Saleem et al.

Myeloid-Specific JAK2 Contributes to Inflammation and Salt Sensitivity of Blood Pressure
Mohammad Saleem; Luul A. Aden; Ashley L. Mutchler; Chitra Basu; Lale A. Ertuglu; Quanhu Sheng; Niki Penner; Anna R. Hemnes; Jennifer H. Park; Jeanne A. Ishimwe; Cheryl L. Laffer; Fernando Elijovich; Celestine N. Wanjalla; Nestor de la Visitacion; Paul D. Kastner; Claude F. Albritton; Taseer Ahmad; Alexandria P. Haynes; Justin Yu; Meghan K. Graber; Sharia Yasmin; Kay-Uwe Wagner; Peter P. Sayeski; Antonis K. Hatzopoulos; Eric R. Gamazon; Alexander G. Bick; Thomas R. Kleyman; Annet Kirabo

BACKGROUND
Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP.

METHODS
We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c+ JAK2 knockout mouse model and measured blood pressure with radiotelemetry after N-omega-nitro-L-arginine-methyl ester and a high salt diet treatment. We used flow cytometry for immunophenotyping and measuring cytokine levels. Fluorescence in situ hybridization and immunohistochemistry were performed to spatially visualize the kidney’s immune cells and cytokine levels. Echocardiography was performed to assess cardiac function.

RESULTS
We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c+ APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acted downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and proinflammatory cytokine IL (interleukin)-6 in renal APCs, which activate T cells and increase production of IL-17A, IL-6, and TNF-α (tumor necrosis factor-alpha).

CONCLUSIONS
Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.

Link | PDF (Circulation Research) [Open Access]

 

In 2018 I was diagnosed with secondary polycythaemia after a negative JAK2 test. From the limited amount I can understand from this, it's interesting on the hypertension. Although I'm very careful about salt intake and haven't been tested, I'm still having twice a day blood pressure tests as mine remains too high. Probably a very silly question from a non-science person, but does a negative JAK2 test specifically rule out any useful reference to blood pressure issues in people with ME/CFS in this research?