Objective

Recently, we observed that the specialized proresolving mediator (SPM) entity resolvin D1 activates lipoxin A₄/formyl peptide receptor 2 (ALX/FPR2), which facilitates cardiac healing and persistent inflammation is a hallmark of impaired cardiac repair in aging. Splenic leukocyte-directed SPMs are essential for the safe clearance of inflammation and cardiac repair after injury; however, the target of SPMs remains undefined in cardiac healing and repair.

Methods

To define the mechanistic basis of ALX/FPR2 as a resolvin D1 target, ALX/FPR2-null mice were examined extensively. The systolic-diastolic heart function was assessed using echocardiography, leukocytes were phenotyped using flow cytometry, and SPMs were quantitated using mass spectrometry. The presence of cardiorenal syndrome was validated using histology and renal markers.

Results

Lack of ALX/FPR2 led to the development of spontaneous obesity and diastolic dysfunction with reduced survival with aging. After cardiac injury, ALX/FPR2^−/− mice showed lower expression of lipoxygenases (−5, −12, −15) and a reduction in SPMs in the infarcted left ventricle and spleen, indicating nonresolving inflammation. Reduced SPM levels in the infarcted heart and spleen are suggestive of impaired cross-talk between the injured heart and splenic leukocytes, which are required for the resolution of inflammation. In contrast, cyclooxygenases (−1 and −2) were over amplified in the infarcted heart. Together, these results suggest interorgan signaling in which the spleen acts as both an SPM biosynthesizer and supplier in acute heart failure. ALX/FPR2 dysfunction magnified obesogenic cardiomyopathy and renal inflammation (↑NGAL, ↑TNF-α, ↑CCL2, ↑IL-1β) with elevated plasma creatinine levels in aging mice. At the cellular level, ALX/FPR2^−/− mice showed impairment of macrophage phagocytic function ex-vivo with expansion of neutrophils after myocardial infarction.

Conclusions

Lack of ALX/FPR2 induced obesity, reduced the life span, amplified leukocyte dysfunction, and facilitated profound interorgan nonresolving inflammation. Our study shows the integrative and indispensable role of ALX/FPR2 in lipid metabolism, cardiac inflammation–resolution processes, obesogenic aging, and renal homeostasis.

中文翻译：

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缺乏分辨率传感器会导致与年龄相关的心脏代谢和心肾缺陷，并阻碍心力衰竭的炎症消退。

客观的

最近，我们观察到专门的促分解介质 (SPM) 实体 resolvin D1 激活脂氧素 A ₄ /甲酰肽受体 2 (ALX/FPR2)，促进心脏愈合，持续性炎症是衰老过程中心脏修复受损的标志。以脾白细胞为导向的 SPM 对于安全清除炎症和损伤后的心脏修复至关重要；然而，SPMs 在心脏愈合和修复方面的目标仍未确定。

方法

为了将 ALX/FPR2 的机制基础定义为 resolvin D1 靶标，对 ALX/FPR2-null 小鼠进行了广泛检查。使用超声心动图评估收缩-舒张心脏功能，使用流式细胞术对白细胞进行表型分析，使用质谱法对 SPM 进行定量。使用组织学和肾脏标志物验证了心肾综合征的存在。

结果

ALX/FPR2 的缺乏导致自发性肥胖和舒张功能障碍的发展，随着年龄的增长而降低存活率。心脏损伤后，ALX/FPR2 ^-/-小鼠表现出较低的脂氧合酶表达（-5、-12、-15）和梗塞的左心室和脾脏中 SPM 的减少，表明炎症无法消退。梗塞心脏和脾脏中 SPM 水平降低表明受损心脏和脾脏白细胞之间的串扰受损，这是消退炎症所必需的。相反，环氧合酶（-1 和-2）在梗塞心脏中过度扩增。总之，这些结果表明，脾脏在急性心力衰竭中既是 SPM 生物合成器，也是供应商。ALX/FPR2 功能障碍会加剧肥胖性心肌病和肾脏炎症（↑NGAL、↑TNF-α、↑CCL2、↑IL-1β），并伴有老年小鼠血浆肌酐水平升高。在细胞水平上，ALX/FPR2 ^-/-小鼠在心肌梗塞后表现出离体巨噬细胞吞噬功能受损，中性粒细胞扩增。

结论

缺乏 ALX/FPR2 会导致肥胖，缩短寿命，加剧白细胞功能障碍，并促进严重的器官间非解决性炎症。我们的研究表明 ALX/FPR2 在脂质代谢、心脏炎症消退过程、肥胖老化和肾脏稳态中的综合和不可或缺的作用。