FRI613 Sex Differences In Human Islet Transcriptional Responses To Inflammation

Abstract

Abstract Disclosure: K.L. Webster: None. W. Wu: None. B. Webb-Robertson: None. E. Nakayasu: None. S. Sarkar: None. C. Evans-Molina: None. S.A. Tersey: None. J. Enriquez: None. S.R. Hammes: None. R.G. Mirmira: None. Higher female incidence of autoimmune disease is often attributed to sex hormone-immune cell interactions or X chromosome immune genes escaping inactivation. Type 1 diabetes (T1D), however, occurs slightly more often in males, and studies show that female sex protects beta cell health under conditions of stress. It is now thought that beta cells themselves trigger loss of immune tolerance in T1D and that the state of beta cell differentiation and health dictates their susceptibility to autoimmunity. Here, we hypothesized that sex influences beta cell response to inflammation during T1D development. We utilized prior bulk RNA sequencing data on human islets from 10 donors (6 males, 4 females) treated for 18h with or without proinflammatory cytokines (PIC: IL-1b, IFNy) to mimic T1D inflammation. Hierarchical clustering grouped samples largely by PIC treatment but also by sex. To identify differentially expressed genes (DEGs) for each sex in response to PIC, we filtered for genes with fold change>1.5 and false discovery rate<0.05. A total of 3754 DEGs were detected in male islets with PIC treatment, while just 1117 were detected in female islets. Of these, 1016 genes were shared between sexes, and many related to cytokine signaling and immune responses. Only 101 DEGs were unique to females, and these were enriched in terms related to leukocyte aggregation, glutamate signaling, and responses to steroid hormone stimuli. 2738 DEGs unique to males were enriched in terms related to inflammation, NOTCH signaling, differentiation, and estrogen biosynthesis. Notably, the gene encoding double-stranded RNA sensor MDA5 (Ifih1), whose activity induces antiviral type I IFN responses and has been linked to T1D, showed a greater average increase with PIC in males (9.99-fold vs. 6.64-fold in females, p<0.05). By gene set enrichment analysis, control and PIC-treated female islets were enriched in differentiation and development pathways, while male islets were enriched in protein translation and steroid metabolism. To probe the role of sex steroid signaling in islet inflammatory response, we measured expression of Esr1 (encoding ERa) via qRT-PCR in mouse islets in response to PIC (IFNy, IL-1b, TNFa). In non-diabetic C57BL6/J mice, islets from both males and females increased Esr1 with PIC (3.63- and 4.39-fold, p<0.05). However, in pre-diabetic NOD mice, in which female mice are highly susceptible to autoimmune diabetes, islets from neither sex increased Esr1. Interestingly, islets from C57BL6/J mice of both sexes decreased expression of Ar (encoding androgen receptor) upon PIC treatment, a response also absent in NOD mice. These data suggested that Esr1 might be protective- and Ar detrimental- for beta cell function, but not in a sex-dependent manner. Collectively, these data demonstrate a sexual dimorphism in islet response to inflammation, with evidence of a more aggressive inflammatory response in males. Presentation: Friday, June 16, 2023