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bioRxiv · 10.1101/2025.10.06.680429

Islet-intrinsic sex differences in inflammatory signaling contribute to autoimmune diabetes susceptibility

Webster, K. L.·Puente, A. A.·Enriquez, J. R.·Sarkar, S.·Nakayasu, E. S.·Webb-Robertson, B.-J. M.·Bramer, L. M.·Figatner, K.·Pratuangtham, S.·Wu, W.·Evans-Molina, C.·Tse, H. M.·Roy, S.·Piganelli, J. D.·Hammes, S. R.·Tersey, S. A.·Mirmira, R. G.
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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 {beta} 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 {beta} cells with the sex hormone 17{beta}-estradiol (E2) suppressed inflammatory signaling and markers of {beta}-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 {beta} 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 {beta}-cell reprogramming reduces {beta}-cell immunogenicity and promotes local immune tolerance, offering mechanistic insight into sex-biased T1D susceptibility.

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Webster, K. L., Puente, A. A., Enriquez, J. R., Sarkar, S., Nakayasu, E. S., Webb-Robertson, B.-J. M., Bramer, L. M., Figatner, K., Pratuangtham, S., Wu, W., Evans-Molina, C., Tse, H. M., Roy, S., Piganelli, J. D., Hammes, S. R., Tersey, S. A., Mirmira, R. G.. 2025-10-07. Islet-intrinsic sex differences in inflammatory signaling contribute to autoimmune diabetes susceptibility. https://doi.org/10.1101/2025.10.06.680429

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