Abstract
BackgroundA high-salt diet (HSD) is one of the major risk factors for acute ischemic stroke (AIS). As a potential mechanism, surplus salt intake primes macrophages towards a proinflammatory phenotype. In this study, whether HSD could blunt the efferocytic capability of macrophages after ischemic stroke, thus exacerbating post-stroke neural inflammation, was investigated.MethodsWild-type male C57BL/6 mice were fed with fodder containing 8% sodium chloride for 4 weeks and subjected to transient middle cerebral occlusion (tMCAO). Disease severity, macrophage polarization as well as efferocytic capability were evaluated. Bone marrow-derived macrophages were cultured in vitro, and the impact of high salinity on their efferocytic activity, as well as their expression of phagocytic molecules, were analyzed. The relationships among sodium concentration, macrophage phenotype, and disease severity in AIS patients were explored.ResultsHSD-fed mice displayed increased infarct volume and aggravated neurological deficiency. Mice fed with HSD suffered exacerbated neural inflammation as shown by higher inflammatory mediator expression and immune cell infiltration levels. Infiltrated macrophages within stroke lesions in HSD-fed mice exhibited a shift towards proinflammatory phenotype and impaired efferocytic capability. As assessed with a PCR array, the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a receptor relevant to phagocytosis, was downregulated in high-salt-treated bone marrow-derived macrophages. Enhancement of TREM2 signaling restored the efferocytic capacity and cellular inflammation resolution of macrophages in a high salinity environment in vitro and in vivo. A high concentration of urine sodium in AIS patients was found to be correlated with lower TREM2 expression and detrimental stroke outcomes.ConclusionsHSD inhibited the efferocytic capacity of macrophages by downregulating TREM2 expression, thus impeding inflammation resolution after ischemic stroke. Enhancing TREM2 signaling in monocytes/macrophages could be a promising therapeutic strategy to enhance efferocytosis and promote post-stroke inflammation resolution.
Highlights
A high-salt diet (HSD) is one of the major risk factors for acute ischemic stroke (AIS)
Excess salt intake exacerbates disease outcomes of ischemic stroke Healthy wild-type (WT) C57BL/6 male mice were fed with a high-salt diet (HSD) or normal diet (ND) for 28 days
We observed increased expression of salt-inducible kinase1 (SIK1) in the ipsilateral brain of HSD mice at 3 days after transient middle cerebral artery occlusion (tMCAO) (Supplementary Figure 1A-B), which was a direct effect of sodium stimulation [23] and revealed the salinized microenvironment in stroke lesion of HSD mice
Summary
A high-salt diet (HSD) is one of the major risk factors for acute ischemic stroke (AIS). Surplus salt intake primes macrophages towards a proinflammatory phenotype. High-salt intake is positively correlated with blood pressure, blood lipid concentration, circulating alarmins, and other factors leading to detrimental stroke prognosis. The habit of high-salt diet (HSD) has long been considered as a risk factor for acute ischemic stroke (AIS) [1,2,3]. Recent research has elucidated that surplus dietary salt shifts macrophages/microglia towards the classical activated proinflammatory phenotype, which is often referred to as M1 [11], indicating that excessive salt intake breaks the M1/M2 macrophages balance and further aggravates the inflammatory response. The impact of HSD on phagocytic activity and the subsequent anti-inflammatory functions of macrophages remain elusive
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