IL-1beta promotes the age-associated decline of beta cell function

Abstract

Aging is the prime risk factor for the development of type 2 diabetes. We investigated the role of the interleukin-1 (IL-1) system on insulin secretion in aged mice. During aging, expression of the protective IL-1 receptor antagonist decreased in islets, whereas IL-1beta gene expression increased specifically in the CD45 + islet immune cell fraction. One-year-old mice with a whole-body knockout of IL-1beta had higher insulin secretion in vivo and in isolated islets, along with enhanced proliferation marker Ki67 and elevated size and number of islets. Myeloid cell-specific IL-1beta knockout preserved glucose-stimulated insulin secretion during aging, whereas it declined in control mice. Isolated islets from aged myeloIL-1beta ko mice secreted more insulin along with increased expression of Ins2, Kir6.2, and of the cell-cycle gene E2f1. IL-1beta treatment of isolated islets reduced E2f1, Ins2, and Kir6.2 expression in beta cells. We conclude that IL-1beta contributes the age-associated decline of beta cell function.

Attenuation of OX40 signaling suppression by age disrupts peripheral deletion of CD4+ T cells specific for the epidermal autoantigen desmoglein 3

“…The reason for this increase is unclear, but it may be related to changes in the expression of cytokines, such as IL-1α/β, which are inducers of OX40 expression [ 33 ]. In fact, increased IL-1β levels has been reported in tissues other than the skin or SLN and IL-1β gene expression was shown to be increased in the CD45 + immune cell fraction in pancreatic islets with age [ 34 ]. In addition, the levels of plasma IL-1β, produced in the lung and spleen, increased after intraperitoneal injection of lipopolysaccharide in aged mice [ 35 ].…”

The cephalic phase of insulin release is modulated by IL-1β

“…Therefore, we performed the cephalic phase 4E, 4F, and S3B), arguing against Lyz2-expressing myeloid cells as a cellular source for cephalic phase IL-1b. However, while highly expressed in peripheral tissue macrophages and monocytes (Bo ¨ni-Schnetzler et al, 2021), the Lyz2-Cre promoter shows only about 45% recombination efficiency in microglia (Goldmann et al, 2013). In support of a central source for IL-1b, refeeding of WT mice induced an increase of Il1b gene expression in microglia sorted from the whole brain (Figure 4G).…”

The Cephalic Phase of Insulin Release is Modulated by Il-1β

“…However, similar to the IL-1b effect described above, IL-1Ra also leaked into the systemic circulation (Figure 4D), even at a 10-fold lower dose (Figure S3A). Therefore, we performed the cephalic phase 4E, 4F, and S3B), arguing against Lyz2-expressing myeloid cells as a cellular source for cephalic phase IL-1b.However, while highly expressed in peripheral tissue macrophages and monocytes (Bo ¨ni-Schnetzler et al, 2021), the Lyz2-Cre promoter shows only about 45% recombination efficiency in microglia (Goldmann et al, 2013). In support of a central source for IL-1b,refeeding of WT mice induced an increase of Il1b gene expression in microglia sorted from the whole brain (Figure 4G).…”