Baumer Yvonne, Singh Komudi, Saurabh Abhinav, Baez Andrew S, Gutierrez-Huerta Cristhian A, Chen Long, Igboko Muna, Turner Briana S, Yeboah Josette A, Reger Robert N, Ortiz-Whittingham Lola R, Joshi Sahil, Andrews Marcus R, Aquino Peterson Elizabeth M, Bleck Christopher Ke, Mendelsohn Laurel G, Mitchell Valerie M, Collins Billy S, Redekar Neelam R, Kuhn Skyler A, Combs Christian A, Pirooznia Mehdi, Dagur Pradeep K, Allan David Sj, Schwartz Daniella M, Childs Richard W, Powell-Wiley Tiffany M
Social Determinants of Obesity and Cardiovascular Risk Laboratory.
Bioinformatics and Computational Core Facility.
JCI Insight. 2024 Dec 24;10(2):e180606. doi: 10.1172/jci.insight.180606.
African American (AA) women are disproportionately affected by obesity and hyperlipidemia, particularly in the setting of adverse social determinants of health (aSDoH) that contribute to health disparities. Obesity, hyperlipidemia, and aSDoH appear to impair NK cells. As potential common underlying mechanisms are largely unknown, we sought to investigate common signaling pathways involved in NK cell dysfunction related to obesity and hyperlipidemia in AA women from underresourced neighborhoods. We determined in freshly isolated NK cells that obesity and measures of aSDoH were associated with a shift in NK cell subsets away from CD56dim/CD16+ cytotoxic NK cells. Using ex vivo data, we identified LDL as a marker related to NK cell function in an AA population from underresourced neighborhoods. Additionally, NK cells from AA women with obesity and LDL-treated NK cells displayed a loss in NK cell function. Comparative unbiased RNA-sequencing analysis revealed DUSP1 as a common factor. Subsequently, chemical inhibition of Dusp1 and Dusp1 overexpression in NK cells highlighted its significance in NK cell function and lysosome biogenesis in a mTOR/TFEB-related fashion. Our data demonstrate a pathway by which obesity and hyperlipidemia in the setting of aSDoH may relate to NK cell dysfunction, making DUSP1 an important target for further investigation of health disparities.
非裔美国（AA）女性受肥胖和高脂血症的影响尤为严重，特别是在那些导致健康差距的不良社会健康决定因素（aSDoH）的背景下。肥胖、高脂血症和aSDoH似乎会损害自然杀伤（NK）细胞。由于潜在的共同潜在机制在很大程度上尚不清楚，我们试图研究资源匮乏社区的AA女性中与肥胖和高脂血症相关的NK细胞功能障碍所涉及的共同信号通路。我们在新鲜分离的NK细胞中确定，肥胖和aSDoH的指标与NK细胞亚群从CD56dim/CD16+细胞毒性NK细胞的转变有关。利用体外数据，我们在资源匮乏社区的AA人群中确定低密度脂蛋白（LDL）是一种与NK细胞功能相关的标志物。此外，肥胖的AA女性的NK细胞和经LDL处理的NK细胞表现出NK细胞功能丧失。比较性无偏RNA测序分析显示双特异性磷酸酶1（DUSP1）是一个共同因素。随后，对NK细胞中Dusp1的化学抑制和Dusp1过表达突出了其在以mTOR/转录因子EB（TFEB）相关方式的NK细胞功能和溶酶体生物发生中的重要性。我们的数据证明了一条途径，通过该途径，aSDoH背景下的肥胖和高脂血症可能与NK细胞功能障碍有关，使DUSP1成为进一步研究健康差距的重要靶点。
