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 6

Dusp1 inhibition rescues LDL-induced lysosome depletion via mTOR and TFEB.

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Dusp1 inhibition rescues LDL-induced lysosome depletion via mTOR and TFE...
Freshly isolated primary NK cells were treated with vehicle, LDL, or LDL+Dusp1inhibitor. (A) RT-qPCR was performed to determine the affect of LDL and its dependency on Dusp1 on mRNA levels of mTOR and TFEB, a transcription factor for lysosomal biogenesis (mTOR, n = 6, repeated-measures 1-way ANOVA with Holm-Šidák correction; TFEB, n = 8, Friedman’s test with Dunn correction). (B) Western Blot analysis of TFEB and β-actin expression. No overall expression differences were observed. Seven of 10 blots displayed a lower TFEB band, indicating decreased TFEB phosphorylation (n = 10). (C) Visualization of TFEB expression utilizing immunofluorescence of TFEB (red) to the nuclei (blue). Yellow arrows indicate translocalization of TFEB. Lysosomes were labeled in green (n = 3). Scale bar: 10 μm. (D and E) Freshly isolated primary NK cells from individuals with or without obesity (W/O vs. WO/O) were subjected to RT-qPCR and Western blotting analysis. (D) RT-qPCR was used to determine potential differences in MTOR and TFEB mRNA expression in obesity (n = 5 WO/O, n = 7 W/O; unpaired 2-tailed t test for each primer). (E) Western blotting was used to examine changes in TFEB expression in NK cells isolated from individuals with or without obesity. (n = 4 WO/O, n = 5 W/O; unpaired 2-tailed t test for each protein). (F) Graphical summary of the findings in this figure. Significance was established at P < 0.05, comparing individual groups, and is indicated by asterisks. *P < 0.05; **P < 0.01; ****P < 0.0001.