Kandarp H Shah1, Peng Shi1, Jorge F Giani1, Tea Janjulia1, Ellen A Bernstein1, You Li1, Tuantuan Zhao1, David G Harrison1, Kenneth E Bernstein1, Xiao Z Shen2. 1. From the Departments of Biomedical Sciences (K.H.S., J.F.G., T.J., E.A.B., T.Z., K.E.B., X.Z.S.), Pathology (K.E.B., X.Z.S.), and Neurology (P.S., Y.L.), Cedars-Sinai Medical Center, Los Angeles, CA; and Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (D.G.H). 2. From the Departments of Biomedical Sciences (K.H.S., J.F.G., T.J., E.A.B., T.Z., K.E.B., X.Z.S.), Pathology (K.E.B., X.Z.S.), and Neurology (P.S., Y.L.), Cedars-Sinai Medical Center, Los Angeles, CA; and Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (D.G.H). xiao.shen@cshs.org.
Abstract
RATIONALE: Chronic inflammation is a major contributor to the progressive pathology of hypertension, and T-cell activation is required for the genesis of hypertension. However, the precise role of myeloid cells in this process is unclear. OBJECTIVE: To characterize and understand the role of peripheral myeloid cells in the development of hypertension. METHODS AND RESULTS: We examined myeloid cells in the periphery of hypertensive mice and found that increased numbers of CD11b(+)Gr1(+) myeloid cells in blood and the spleen are a characteristic of 3 murine models of experimental hypertension (angiotensin II, L-NG-nitroarginine methyl ester, and high salt). These cells express surface markers and transcription factors associated with immaturity and immunosuppression. Also, they produce hydrogen peroxide to suppress T-cell activation. These are characteristics of myeloid-derived suppressor cells (MDSCs). Depletion of hypertensive MDSCs increased blood pressure and renal inflammation. In contrast, adoptive transfer of wild-type MDSCs to hypertensive mice reduced blood pressure, whereas the transfer of nicotinamide adenine dinucleotide phosphate oxidase 2-deficient MDSCs did not. CONCLUSION: The accumulation of MDSCs is a characteristic of experimental models of hypertension. MDSCs limit inflammation and the increase of blood pressure through the production of hydrogen peroxide.
RATIONALE: Chronic inflammation is a major contributor to the progressive pathology of hypertension, and T-cell activation is required for the genesis of hypertension. However, the precise role of myeloid cells in this process is unclear. OBJECTIVE: To characterize and understand the role of peripheral myeloid cells in the development of hypertension. METHODS AND RESULTS: We examined myeloid cells in the periphery of hypertensivemice and found that increased numbers of CD11b(+)Gr1(+) myeloid cells in blood and the spleen are a characteristic of 3 murine models of experimental hypertension (angiotensin II, L-NG-nitroarginine methyl ester, and high salt). These cells express surface markers and transcription factors associated with immaturity and immunosuppression. Also, they produce hydrogen peroxide to suppress T-cell activation. These are characteristics of myeloid-derived suppressor cells (MDSCs). Depletion of hypertensive MDSCs increased blood pressure and renal inflammation. In contrast, adoptive transfer of wild-type MDSCs to hypertensivemice reduced blood pressure, whereas the transfer of nicotinamide adenine dinucleotide phosphate oxidase 2-deficient MDSCs did not. CONCLUSION: The accumulation of MDSCs is a characteristic of experimental models of hypertension. MDSCs limit inflammation and the increase of blood pressure through the production of hydrogen peroxide.
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