Abstract
Hypertension is considered the major modifiable risk factor for the development of cognitive impairment. Because increased blood pressure is often accompanied by an activation of the immune system, the concept of neuro-inflammation gained increasing attention in the field of hypertension-associated neurodegeneration. Particularly, hypertension-associated elevated circulating T-lymphocyte populations and target organ damage spurred the interest to understanding mechanisms leading to inflammation-associated brain damage during hypertension. The present study describes sphingosine-1-phosphate (S1P) as major contributor to T-cell chemotaxis to the brain during hypertension-associated neuro-inflammation and cognitive impairment. Using Western blotting, flow cytometry and mass spectrometry approaches, we show that hypertension stimulates a sphingosine kinase 1 (SphK1)-dependent increase of cerebral S1P concentrations in a mouse model of angiotensin II (AngII)-induced hypertension. The development of a distinct S1P gradient between circulating blood and brain tissue associates to elevated CD3+ T-cell numbers in the brain. Inhibition of S1P1-guided T-cell chemotaxis with the S1P receptor modulator FTY720 protects from augmentation of brain CD3 expression and the development of memory deficits in hypertensive WT mice. In conclusion, our data highlight a new approach to the understanding of hypertension-associated inflammation in degenerative processes of the brain during disease progression.
Highlights
Hypertension is the leading cause of disease burden in the developed world and a major modifiable risk factor for the development of several degenerative conditions in target organs [1,2]
It became apparent that hypertension associates to an activation of the immune system with a critical involvement of T-lymphocytes in its pathogenesis [4,5,6,7,8]
Such chronic inflammation contributes to progression of hypertension [6,7,8] and unfavourably affects target organs, including the brain [9,10,11,12]
Summary
Hypertension is the leading cause of disease burden in the developed world and a major modifiable risk factor for the development of several degenerative conditions in target organs [1,2]. Besides the existing association between elevated levels of pro-inflammatory cytokines such as Interleukin (IL)-6 or C reactive protein and cognitive impairment [16,17], studies have shown an augmentation of circulating T-cell numbers in patients with various neurodegenerative diseases [18] and an infiltration of T-lymphocytes into the brain of patients with Parkinson’s and Alzheimer’s disease [19,20,21] These studies point to a critical involvement for T-cell infiltration to increasing disease burden and describe potential direct detrimental effects on cognitive function, the mechanism by which T-lymphocytes home to the brain remains to be determined. The exact interplay between immune system activation during hypertension and degenerative consequences of hypertension in the brain is still elusive
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