This study reveals that JAK2 in myeloid-derived CD11c+ antigen-presenting cells (APCs) promotes salt-sensitive hypertension through the STAT3 and SMAD3 signaling pathways, providing a novel potential target for diagnosing and treating salt-sensitive hypertension.
Literature Overview
The article "Myeloid-Specific JAK2 Contributes to Inflammation and Salt-Sensitivity of Blood Pressure", published in Circulation Research, reviews the role and mechanisms of JAK2 in salt-sensitive hypertension. Using transcriptomic analysis of human monocytes and mouse models, flow cytometry, FISH, and immunohistochemistry (IHC), it uncovers how the JAK2-STAT3-SMAD3 signaling axis drives inflammation and hypertension in salt-sensitive individuals.
Background Knowledge
Salt-sensitive blood pressure (SSBP) is a phenotype where blood pressure fluctuates significantly with dietary sodium intake, independently associated with cardiovascular diseases and mortality. Previous studies indicate that high sodium intake induces hypertension by activating antigen-presenting cells (APCs), but the precise mechanisms remain unclear. This research focuses on JAK2 function in CD11c+ APCs, demonstrating its activation of STAT3 and SMAD3 pathways to enhance pro-inflammatory cytokines and isolevuglandin (IsoLG) production, subsequently activating T cells and releasing IL-17A, IL-6, and TNF-α. Additionally, gene knockout mouse models validate JAK2's critical role in salt-sensitive hypertension, with pathway activation confirmed via flow cytometry, FISH, and Western blot. The study provides new insights into the immunological mechanisms of SSBP and potential molecular targets for future therapies.
Research Methods and Experiments
Researchers analyzed gene expression changes in human monocytes under high-salt conditions using bulk RNA sequencing and single-cell sequencing (CITE-Seq). They developed CD11c+ cell-specific JAK2 knockout mouse models and monitored blood pressure via radiotelemetry. Flow cytometry assessed immune cell phenotypes and cytokine levels, while FISH and IHC evaluated renal immune cell distribution and gene expression. Cardiac function was analyzed by ECHO, supported by Western blot and statistical validation of pathway activation.
Key Conclusions and Perspectives
Research Significance and Prospects
This study identifies JAK2 in myeloid-derived CD11c+ APCs as a pivotal regulator of salt-sensitive hypertension via STAT3/SMAD3 pathways, offering new diagnostic and therapeutic targets. Future work may explore JAK2 inhibitors or immunomodulatory strategies targeting CD11c+ APCs. This mechanism could extend to other inflammation-associated hypertension models and support personalized treatment approaches.
Conclusion
This study establishes that JAK2 in bone marrow-derived antigen-presenting cells (APCs) exacerbates salt-sensitive hypertension through STAT3 and SMAD3 signaling. High-salt environments elevate JAK2 expression, activating downstream pathways that amplify IsoLG and pro-inflammatory cytokines like IL-6, subsequently stimulating T cells and increasing IL-17A and TNF-α. JAK2 knockout mouse models demonstrate reduced salt-induced hypertension, renal immune infiltration, and fibrosis. Transplantation experiments confirm JAK2 in CD11c+ APCs as a critical mediator of salt sensitivity. These findings offer mechanistic insights into SSBP immunobiology and lay the groundwork for targeting JAK2 pathways in therapeutic strategies. Future studies should evaluate this pathway's expression across populations and its potential as a biomarker for precision medicine.
