Mulberroside A inhibits NLRP6 to prevent alveolar macrophage efferocytosis and lung-derived SAA3-platelet transport in high fructose-induced hippocampal inflammation

Introduction: High fructose is reported to induce lung and hippocampus inflammatory injury. Mulberroside A, derived from the traditional Chinese herb Cortex mori, which is commonly used to treat coughs and bronchitis, has anti-inflammation and neuroprotection.

Objectives: This study aimed to explore whether and how mulberroside A prevent high fructose-induced lung injury and hippocampal inflammation.

Methods: Mice and cultured MH-S, a murine alveolar macrophage cell line were treated with high fructose and/or mulberroside A and positive drug dipyridamole, respectively. Alveolar macrophages (AMs) efferocytosis function, NOD-like Receptor family pyrin domain containing 6 (NLRP6) and serum amyloid A3 (SAA3) level were evaluated by Western blot, real-time quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence, respectively. Nlrp6^-/- mice and Nlrp6 overexpression MH-S cells were used to explore the contribution of NLRP6 to AMs efferocytosis dysfunction and hippocampal inflammation under high fructose stimulation, respectively. Simultaneously, a fluorescent anti-GPIbβ Ab (X488) was used to label platelets in mice for measuring lung-derived SAA3 level in platelets.

Results: High fructose caused AMs efferocytosis dysfunction, and up-regulated NLRP6 expression in lung inflammation of mice. SAA3 was found to be abundantly expressed in AMs of fructose-fed mice. Whereas, lung-derived SAA3 transport via platelets induced blood-brain barriers (BBB) injury and hippocampal inflammation in this animal model. Nlrp6 promoted AMs efferocytosis dysfunction and lung-derived SAA3 transport via platelets to induce hippocampal inflammation under high fructose condition. More important, mulberroside A decreased lung NLRP6 expression, and then enhanced AMs efferocytosis function and inhibited lung inflammation. Meanwhile, they blocked lung-derived SAA3-platelet transportation to prevent hippocampal inflammation in high fructose-fed mice.

Conclusion: These results suggested that mulberroside A inhibited NLRP6 to prevent alveolar macrophage efferocytosis and lung-derived SAA3-platelet transport in high fructose-induced hippocampal inflammation.

Dipyridamole; Efferocytosis; Hippocampal inflammation; Mulberroside A; NLRP6; SAA3.