Pathways that mitigate cellular stress are critical for pancreatic beta cell function and survival. We have reported that the cytokine interleukin-6 (IL-6) coordinately activates two such pathways, autophagy and the antioxidant response, resulting in decreased oxidative stress and increased beta cell survival under diabetogenic conditions. Our investigation of this protective effect of IL-6 on the beta cells subsequently revealed that members of the IL-6 family of cytokines stimulated the mitochondrial translocation of NRF2, the central antioxidant regulator. This was surprising since NRF2 is well-characterized as a transcription factor. Under these conditions, we also observe translocation of another transcription factor, STAT3, to the mitochondria, consistent with previously published observations. Here, we present data to validate these findings in the islet in vivo and investigate the downstream events associated with NRF2 mitochondrial translocation. We used a mouse model where animals were intraperitoneally injected with either IL-6 or another IL-6 family member, leukemia inhibitory factor (LIF), and pancreata were collected at 30 minutes post-injection. We then used immunofluorescence analysis of paraffin tissue sections. We observed that both IL-6 and LIF rapidly elicit a reduction in the autophagy receptor p62 both in the cytosol and at the mitochondria when compared to saline-injected mice. This suggests that both global autophagy and selective mitophagy are stimulated in the beta cell by both IL-6 and LIF. Furthermore, as both IL-6 and LIF selectively stimulate mitochondrial but not nuclear translocation of NRF2, our data suggests that NRF2 may play a role in the stimulation of mitophagy by IL-6 family cytokines. Further studies investigating the requirement of NRF2 for beta cell mitophagy under conditions of beta cell stress response will shed light on this novel pathway of the cellular antioxidant response.
M. Marasco: Employee; Spouse/Partner; Eli Lilly and Company. Z. Akbar: None. J. Crowder: Employee; Spouse/Partner; Eli Lilly and Company. A. Novak: None. C. Muralidharan: None. M. Arvin: None. A.K. Linnemann: None.
National Institutes of Health (T32DK064466-16, R03DK115990)