Discussion High salt and Stroke
The current study demonstrates that a microenvironment with an excess salt concentration could impair the inflammation resolution property of macrophages after ischemic stroke. Mechanistically, excessive salt downregulates TREM2 expression in macrophages associated with decreased efferocytic capacity, excessive neural inflammation, and exacerbated stroke outcomes.
Given the diverse and broad effect of sodium ions,
histocytes and the urinary system keep sodium in strict equilibrium.
For being fed with the high-salt diet for as long as 4 weeks, sodium concentration in the peripheral blood and interstitial fluid of HSD mice still remained stable.
It remains to be demonstrated whether smaller changes in Na concentration have similar effects on macrophage function. The transient fluctuation of sodium concentration along with daily meals, which are insistently repeated during the high-salt diet, could be sufficient to exert effective impacts. In accordance, we recorded that circulating monocytes in stroke patients with high-salt consumption displayed proinflammatory inclination compared with those in patients with appropriate salt intake,
which was presented in culture macrophages directly exposed to a high-salt environment in vitro.
Further, in the arena of stroke lesion, ongoing neural inflammation and local metabolic disturbance could facilitate sodium accumulation.
Excessive expression of SIK1 in stroke lesion of HSD mice revealed the salinized microenvironment encountered
by the infiltrated macrophages. To explore the molecular mechanisms of functional alterations of macrophages when encountering sodium stimulation, bone marrow-derived macrophages were cultured and
threatened with high sodium treatment. Although the in vitro culture system failed to perfectly reproduce the complicated and dynamic pathophysiological process
in vivo, we recorded distinctive proinflammatory
activations in high-salt-treated macrophages, which were further verified in HSD stroke mice and AIS patients.
It has been reported that the HSD could promote BBB injury after ischemic stroke [12].
Consistently, we recorded that increased infiltration of multiple leukocytes, including macrophages, neutrophils, T lymphocytes, and B lymphocytes, in the stroke lesions of HSD mice at 3 days after stroke, could be attributed to the exacerbated BBB damage. It was found that surplus dietary salt directed macrophages/microglia towards the classical activated “M1” phenotype, which further exacerbated stroke outcomes [24].
In accordance, our data indicated that the inflammation resolution property of macrophages was downregulated by excess salt, which led to the postponed recovery of stroke lesions.Efferocytosis represents an essential process of inflammation resolution [32, 33].
Elimination of the dead or injured components
within stroke lesion arrests amplification of neural inflammation.
We demonstrated that the efferocytic capacity, together with the subsequent cellular inflammation resolution of macrophages, was impaired in the high salinity environment, which could be a rational explanation for accumulated dead cells in the stroke penumbra.
It has been demonstrated that the function of TREM2 is indispensable for phagocytic activities of microglia and macrophages [34]. Our data indicated that TREM2 was downregulated in macrophages in the high salinity environment. Decreased TREM2 expression was correlated with robust post-stroke neural inflammation and exacerbated stroke outcomes, which indicated that inhibition of TREM2 signaling in macrophages was the potential mechanism involved in the detrimental impact of the high-salt microenvironment.
It has been recognized that HSD is a crucial risk factor for ischemic stroke. Restriction of dietary salt intake serves as an efficient and practical method for preventing new vascular events. Nevertheless, no niched therapy that targets the already impaired inflammation resolution property of macrophages in the high-salt environment has been reported. In our study, utilization of TREM2-overexpressing macrophages offered neuroprotection to HSD mice. In addition, overexpression of TREM2 restored the efferocytic capacity and cellular inflammation resolution of macrophages in a high salinity environment. The data encourage further research on the therapeutic potential of enhancing TREM2 signaling in patients with ischemic stroke, especially those with high-salt intake
Ref
J Neuroinflammation. 2021 Apr 12;18:90.
doi: 10.1186/s12974-021-02144-9
High-salt diet downregulates TREM2 expression and blunts efferocytosis of macrophages after acute ischemic stroke
Mengyan Hu 1,#, Yinyao Lin 1,#, Xuejiao Men 1,#, Shisi Wang 1, Xiaobo Sun 1, Qiang Zhu 1, Danli Lu 1, Sanxin Liu 1, Bingjun Zhang 1, Wei Cai 1,2,✉, Zhengqi Lu 1,✉
