The interplay between loneliness, cortisol, and NK cell function: The role of cortisol in NK cell dysfunction
Year: 2026
Type: article
Abstract: Chronic psychosocial stressors contribute to cardiovascular disease (CVD) and related risk factors, particularly in under-resourced communities. Psychosocial stressors activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to sustained cortisol action on immune cells. Natural killer (NK) cells are altered in distribution and function in cardio-metabolic diseases; however, pathways linking cortisol as a marker of chronic stress to NK cell dysfunction remain understudied. We recruited 186 African American women from the Step It Up Community-Engaged, Digital Health Physical Activity Intervention study and collected cortisol, NK cell measures, and psychosocial stress measures using validated questionnaires, including chronic stress and loneliness. Plasma cortisol levels were negatively associated with NK cell proportions, and self-reported levels of loneliness modified this relationship (p = 0.011); among participants with higher loneliness, higher plasma cortisol levels were associated with lower proliferative NK cell proportions (β=-0.30, p = 0.04). In a subset of study participants (n = 24), plasma cortisol levels were directly associated with a loss of NK cell degranulation (β=-0.38, p = 0.03). Using an RNA sequencing dataset, we found that higher plasma cortisol levels were associated with suppressed gene expression related to NK cell cytotoxicity. Finally, in vitro experiments on freshly isolated primary NK cells revealed that cortisol reduces NK cell degranulation (p = 0.006) via FABP-4-induced upregulation of PD-1 expression (p = 0.01). In summary, our study provides evidence that in individuals with higher loneliness, cortisol may alter NK cell distribution and function. Furthermore, cortisol-mediated NK cell dysfunction may be facilitated in a FABP-4/PD-1 dependent manner, leading to impaired innate immune function and, potentially, contributing to worsening CVD risk.
Source: Psychoneuroendocrinology
Authors: Abhinav Saurabh, Yvonne Baumer, Laurel G. Mendelsohn, Elizabeth M. Aquino Peterson, Dana Sandler, Shirley J. Lopez De Leon, Ayushi Dave, Andrew S. Baez, Lola R. Ortiz-Whittingham, Mario A. Pita, Manuel A. Cintron, Hannatu A. Tarfa, Sandy T. Reynolds, Shelby R. Hicks, Sonal Sharda, J. Eleanor Seo, Maria Lopez-Ocasio, Pradeep K. Dagur, Skyler A. Kuhn, Neelam R. Redekar, James F. Troendle, Ayanna L. Wells, Marie Marah, Katherine J. Tolentino, Michael J. Corley, Alika K. Maunakea, Lynnette K. Nieman, Marcus R. Andrews, Tiffany M. Powell-Wiley
Institutions: National Heart, Lung, and Blood Institute, National Heart, Lung, and Blood Institute Division of Intramural Research, Eastern Virginia Medical School, Old Dominion University, National Institutes of Health, National Institute of Allergy and Infectious Diseases, University of California San Diego, University of Hawaiʻi at Mānoa, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Minority Health and Health Disparities
Language: English
Subfield: Behavioral Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,830
Awards: Genetics and Epigenetics of Cardiovascular Disease, Pilot Study for Geospatial Analysis of Neighborhood Environmental Stress in Relation to Biological Markers of Cardiovascular Health and Health Behaviors in Women, Tailoring Mobile Health Technology to Reduce Obesity and ImproveCardiovascular Health in Resource-Limited Neighborhood Environments: A Multi-Level, Community-Based Physical Activity Intervention, Cardiovascular Health and Needs Assessment in Washington D.C.
OpenAlex ID: W7156326581