Social Determinants modulate NK cell activity via obesity, LDL, and DUSP1 signaling

Yvonne Baumer; Komudi Singh; Andrew S Baez; Christian A Gutierrez-Huerta; Long Chen; Muna Igboko; Briana S Turner; Josette A Yeboah; Robert N Reger; Lola R Ortiz-Whittingham; Christopher K E Bleck; Valerie M Mitchell; Billy S Collins; Mehdi Pirooznia; Pradeep K Dagur; David S J Allan; Daniella Muallem-Schwartz; Richard W Childs; Tiffany M Powell-Wiley

doi:10.1101/2023.09.12.556825

Social Determinants modulate NK cell activity via obesity, LDL, and DUSP1 signaling

bioRxiv [Preprint]. 2023 Sep 15:2023.09.12.556825. doi: 10.1101/2023.09.12.556825.

Authors

Yvonne Baumer¹, Komudi Singh², Andrew S Baez¹, Christian A Gutierrez-Huerta¹, Long Chen³, Muna Igboko³, Briana S Turner¹, Josette A Yeboah¹, Robert N Reger³, Lola R Ortiz-Whittingham¹, Christopher K E Bleck⁴, Valerie M Mitchell¹, Billy S Collins¹, Mehdi Pirooznia², Pradeep K Dagur⁵, David S J Allan³, Daniella Muallem-Schwartz⁶, Richard W Childs³, Tiffany M Powell-Wiley^{1

7}

Affiliations

¹ Social Determinants of Obesity and Cardiovascular Risk Laboratory, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
² Bioinformatics and Computational Core Facility, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
³ Section of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Electron Microscopy Core Facility, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Flow Cytometry Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Intramural Research Program, National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD, USA.

Abstract

Adverse social determinants of health (aSDoH) are associated with obesity and related comorbidities like diabetes, cardiovascular disease, and cancer. Obesity is also associated with natural killer cell (NK) dysregulation, suggesting a potential mechanistic link. Therefore, we measured NK phenotypes and function in a cohort of African-American (AA) women from resource-limited neighborhoods. Obesity was associated with reduced NK cytotoxicity and a shift towards a regulatory phenotype. In vitro, LDL promoted NK dysfunction, implicating hyperlipidemia as a mediator of obesity-related immune dysregulation. Dual specific phosphatase 1 (DUSP1) was induced by LDL and was upregulated in NK cells from subjects with obesity, implicating DUSP1 in obesity-mediated NK dysfunction. In vitro, DUSP1 repressed LAMP1/CD107a, depleting NK cells of functional lysosomes to prevent degranulation and cytokine secretion. Together, these data provide novel mechanistic links between aSDoH, obesity, and immune dysregulation that could be leveraged to improve outcomes in marginalized populations.

Keywords: Cardiovascular disease; Health Disparities; Lipids; Lysosomes; NK cells; Obesity; Social Determinants of Health.

Publication types

Preprint

Grants and funding

T32 GM080202/GM/NIGMS NIH HHS/United States