Obesity modulates NK cell activity via LDL and DUSP1 signaling for populations with adverse social determinants
Yvonne Baumer, Komudi Singh, Abhinav Saurabh, Andrew S. Baez, Cristhian A. Gutierrez-Huerta, Long Chen, Muna Igboko, Briana S. Turner, Josette A. Yeboah, Robert N. Reger, Lola R. Ortiz-Whittingham, Sahil Joshi, Marcus R. Andrews, Elizabeth M. Aquino Peterson, Christopher K.E. Bleck, Laurel G. Mendelsohn, Valerie M. Mitchell, Billy S. Collins, Neelam R. Redekar, Skyler A. Kuhn, Christian A. Combs, Mehdi Pirooznia, Pradeep K. Dagur, David S.J. Allan, Daniella M. Schwartz, Richard W. Childs, Tiffany M. Powell-Wiley
Yvonne Baumer, Komudi Singh, Abhinav Saurabh, Andrew S. Baez, Cristhian A. Gutierrez-Huerta, Long Chen, Muna Igboko, Briana S. Turner, Josette A. Yeboah, Robert N. Reger, Lola R. Ortiz-Whittingham, Sahil Joshi, Marcus R. Andrews, Elizabeth M. Aquino Peterson, Christopher K.E. Bleck, Laurel G. Mendelsohn, Valerie M. Mitchell, Billy S. Collins, Neelam R. Redekar, Skyler A. Kuhn, Christian A. Combs, Mehdi Pirooznia, Pradeep K. Dagur, David S.J. Allan, Daniella M. Schwartz, Richard W. Childs, Tiffany M. Powell-Wiley
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Research Article Cardiology Immunology

Obesity modulates NK cell activity via LDL and DUSP1 signaling for populations with adverse social determinants

Abstract

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.

Authors

Yvonne Baumer, Komudi Singh, Abhinav Saurabh, Andrew S. Baez, Cristhian A. Gutierrez-Huerta, Long Chen, Muna Igboko, Briana S. Turner, Josette A. Yeboah, Robert N. Reger, Lola R. Ortiz-Whittingham, Sahil Joshi, Marcus R. Andrews, Elizabeth M. Aquino Peterson, Christopher K.E. Bleck, Laurel G. Mendelsohn, Valerie M. Mitchell, Billy S. Collins, Neelam R. Redekar, Skyler A. Kuhn, Christian A. Combs, Mehdi Pirooznia, Pradeep K. Dagur, David S.J. Allan, Daniella M. Schwartz, Richard W. Childs, Tiffany M. Powell-Wiley

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Figure 5

Dusp1 affects lysosome biology.

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Dusp1 affects lysosome biology. Dusp1 was overexpressed in NK92 cells. T...
Dusp1 was overexpressed in NK92 cells. The created cell line and its empty vector control were examined to better understand pathways regulated by Dusp1. (A and B) Proteomics analysis of DUSP1-overexpressing (oe) NK92 cells (n = 4 sets). (A) Partial least square discriminant analysis (PLSDA) plot of the proteomics data of DUSP1-overexpressing NK92 cells. (B) Top 15 gene ontology (GO) terms enriched by proteins that discriminate DUSP1oe NK92cells from NK92cells. Each dot is an enriched GO term labeled on the y axis; the size of the dot is scaled to the number of DEGs associated with GO term and is plotted on a negative log10 q value on the x axis. (C–E) Dusp1oe NK92 cells and their controls were examined for LAMP1 mRNA expression (n = 3, unpaired 2-tailed t test), intracellular Lamp-1 protein expression using flow cytometry (n = 6, unpaired 2-tailed t test), and TEM imaging (n = 3 pooled; scale bar: 1 μm). (F–I) Freshly isolated NK cells were treated with vehicle, LDL, or LDL+Dusp1inhibitor. (F) RT-qPCR was performed to determine LAMP1 mRNA levels (n = 7, repeated-measures 1-way ANOVA with Tukey’s correction). (G) Flow cytometry was used to quantify intracellular CD107a expression (n = 10, repeated-measures 1-way ANOVA with Šidák correction). (H) Immunofluorescence analysis of CD107a (red) to determine the presence of intracellular lysosomes, visually confirming flow cytometry results (n = 4). Green = F-actin and blue = DAPI. Scale bar: 10 μm. (I) TEM analysis of n = 3 (pooled). The number of vesicular granules (VG), electron-dense granules (EG), and all granules (VG, EG as well as other granules (OG) was counted per microscopic field and graphed per treatment condition. Representative images are shown. Scale bar: 1 μm. (J) RT-qPCR of freshly isolated NK cells of individuals with or without obesity (W/O, n = 7 vs. WO/O, n = 5) to determine differences in LAMP1 mRNA expression. (K) Graphical summary of the findings in this figure. Significance was established at P < 0.05; asterisks indicate significance between groups. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.