Blocking Type I Interferon Signaling Rescues Lymphocytes from Oxidative Stress, Exhaustion, and Apoptosis in a Streptozotocin-Induced Mouse Model of Type I Diabetes

Abstract

Elevated levels of type I interferon (IFN) during type 1 diabetes mellitus (T1D) are associated with a defective immune response. In the present study, we investigated whether blocking type I IFN signaling during streptozotocin- (STZ-) induced T1D in mice improves lymphocyte proliferation and escape from continuous apoptosis. Three groups of mice were examined: diabetic mice, type I IFN signaling-incompetent diabetic mice, and control nondiabetic mice. We first found that diabetes induction was accompanied by an elevation in the plasma levels of reactive oxygen species (ROS), hydroperoxide, malondialdehyde (MDN), and the proinflammatory cytokines IL-1α, IL-1β, IL-6, and CXCL10. Blocking type 1 IFN signaling in diabetic mice significantly decreased the levels of oxidative stress and proinflammatory cytokines. In addition, lymphocytes from diabetic mice exhibited a marked reduction in their proliferative capacity, increased apoptosis, upregulation of the exhaustion marker PD-1, and aberrant phosphorylation of STAT1, STAT2, AKT and IκB-α. Interestingly, following the blocking of type I IFN signaling in diabetic mice, the lymphocytes exhibited restored proliferative capacity, decreased apoptosis, normal expression of PD-1, and normal phosphorylation of STAT1, STAT2, AKT and IκB-α. Our data suggest that elevated levels of type I IFN during T1D trigger lymphocyte exhaustion and a defective lymphocyte-medicated immune response.

Increased Levels of Type 1 Interferon in a Type 1 Diabetic Mouse Model Induce the Elimination of B Cells from the Periphery by Apoptosis and Increase their Retention in the Spleen

“…We recently investigated the effect of STZ-induced immunosuppression in an animal model [36]. First, pancreatic sections from both STZ-treated and naive mice were stained with H&E and examined by light microscopy.…”

“…Forty Swiss Webster mice were assigned to three experimental groups: group 1, the non-diabetic control group (n=10), was injected with vehicle alone (0.01 M citrate buffer, pH 4.5); group 2, the diabetic group (n=15), was rendered diabetic by intraperitoneal injection of a single dose of STZ (60 mg per kilogram of body weight) in 0.01 M citrate buffer (pH 4.5); group 3 (n=15) was rendered diabetic using the same procedure as in group 2 but was also injected intraperitoneally, one month after diabetes induction, with an anti-IFN (alpha, beta and omega) receptor 1 (IFNAR1) antibody at a dose of 10 mg per kilogram of body weight daily for up to 20 days [36,37]. …”

“…We recently demonstrated that diabetic mice exhibit increased apoptosis, DNA fragmentation, chromatin condensation and cell shrinkage, prolonged elevation of IFN-α and TNF-α levels, and a clear reduction in T lymphocytes homing to the spleen [35]. We have also quantified the relationship between type 1IFN signaling and the survival/death and function of peripheral blood mononuclear cells (PBMCs) during T1D [36]. To better understand the role of IFN-α in the etiology of type 1 diabetes, in the present study we examined the number, distribution and function of peripheral B cells and the MZB compartment in streptozotocin (STZ) mice.…”

The pros and cons of dying tumour cells in adaptive immune responses

“…For example, Wang et al showed that the up regulation of IFNβ expression in dendritic cells promoted antigen presentation but compromised T cell priming 7 . Another study showed that elevated levels of type I IFNs during type 1 diabetes triggered lymphocyte exhaustion and disabled lymphocyte-mediated immune responses 8 . In a tumour-bearing mouse model, IFNα augmented programmed cell death 1 (PD1) expression on antigenspecific CD8 + T cells and thus significantly inhibited T cell-mediated immunity 9 .…”

Evaluation of the Immunotoxic Effects of Sub-Chronic Doses of Lambda-Cyhalothrin in Murine Model

“…Samples were analyzed by flow cytometry using a FACS caliber flow cytometer (BD immune cytometry systems, San Jose, CA). The FL2 red fluorescence channel was assessed on a linear scale, and the percentage of cells undergoing cell death was determined as the percentage of hypodiploid cells (sub G0/G1 peak) [34]. …”