Islet-intrinsic sex differences in inflammatory signaling contribute to autoimmune diabetes susceptibility
Year: 2025
Type: preprint
Abstract: Whereas most autoimmune diseases exhibit female predominance, type 1 diabetes (T1D) occurs more frequently in males after puberty, suggesting a role for sex hormones in disease modification. Because islet β cells actively shape local immune responses, we hypothesized that sex-specific islet responses to inflammation contribute to this disparity. Using transcriptomic and proteomic analyses of human islets from male and female donors, we found that male islets exhibit a more aggressive response to proinflammatory cytokines, characterized by greater induction of interferon signaling and suppression of developmental signaling compared to female islets. Treatment of human islets and mouse β cells with the sex hormone 17β-estradiol (E2) suppressed inflammatory signaling and markers of β-cell maturity while enhancing developmental gene programs. Complementary studies in non-obese diabetic (NOD) mice showed that E2 treatment reduces diabetes incidence and limits progression to severe insulitis. Islet single-cell RNA sequencing revealed that E2 treatment of NOD mice suppresses interferon signaling, chemokine production, and antigen presentation in β cells, while reducing activation and cytotoxicity pathways in immune cells. In co-culture studies in vitro, E2 pretreatment of mouse islets reduces subsequent activation of T cells, and in an aggressive adoptive transfer model in vivo, E2 pretreatment of the recipient mice was found to attenuate hyperglycemia. These findings support a model in which E2-mediated β-cell reprogramming reduces β-cell immunogenicity and promotes local immune tolerance, offering mechanistic insight into sex-biased T1D susceptibility.
Authors: Kierstin L. Webster, Armando A. Puente, Jacob R. Enriquez, Soumyadeep Sarkar, Ernesto S. Nakayasu, Bobbie-Jo M. Webb-Robertson, Lisa M. Bramer, Kayla Figatner, Sarida Pratuangtham, Wenting Wu, Carmella Evans-Molina, Hubert M. Tse, Saptarshi Roy, Jon D. Piganelli, Stephen R. Hammes, Sarah A. Tersey, Raghavendra G. Mirmira
Institutions: University of Chicago, Pacific Northwest National Laboratory, Indiana University Indianapolis, Indiana University School of Medicine, Richard L. Roudebush VA Medical Center, University of Kansas, University of Kansas Medical Center, University of Rochester Medicine, University of Rochester
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: Interferon Signaling in the T1D Islet Microenvironment, The Role of Polyamines and Hypusine in Beta-Cell Dysfunction, An Interdisciplinary Molecular Metabolism Training Program, Polyamines and Hypusine in Type 1 Diabetes Pathogenesis, Immunoengineering Postdoctoral Training Program - Resubmission - 1, Medical Scientist National Research Service Award, Indiana Diabetes Research Center, Transcriptional and Translational Mechanisms Governing Beta Cell Function, Diabetes Research and Training Center
OpenAlex ID: W4414903724