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 1

Obesity associated with differences in NK cell subset profiles and NK cell dysfunction.

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Obesity associated with differences in NK cell subset profiles and NK ce...
Age-matched AA female individuals from resource-limited neighborhoods who did (W/O; BMI ≥ 30 n = 14) or did not present with obesity (WO/O; BMI < 30, n = 15), respectively, were study participants. (A and B) Whole blood was examined by flow cytometry to analyze the lymphocytes, namely, CD19+ B, CD3+/CD56– T, CD3+/CD56+ T, and CD3–/CD56+ NK cell populations. (B) Deeper phenotyping of CD56+ NK cells by CD16 expression allows a general identification of CD56hi/CD16dim/– and CD56dim/CD16hi NK cell phenotypes. (Depending on normality test, either 2-tailed unpaired t test or Mann-Whitney test comparing 2 patient groups for each immune cell population was performed.) (C–I) NK cells were isolated from AA female individuals who did (n = 13) or did not present with obesity (n = 15) and were subjected to the degranulation assay under baseline and activating conditions. For activating conditions (+activator), NK cell Cell Activator Cocktail was added right before the experiment to determine the maximum response of the tested conditions. By using flow cytometry, the proportion of dead K562 cells (C), as a measure of NK cell killing ability under activating conditions; the expression of CD107a (D), as a measure of NK cell degranulation; and the intracellular expression of IFN-γ (E), TNF-α (F), granzyme B (G), perforin (H), and GM-CSF (I) were detected. Statistical significance was determined by using (C, E, F, and H) Mann-Whitney test and (D, G, and I) unpaired (2-tailed) t test. Significance was established at P < 0.05, comparing individual groups with the data-appropriate test; asterisks indicate significance between groups. Flow data are accompanied by representative dot or volcano blots. *P < 0.05; **P < 0.01.