Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

Abstract

In type 1 diabetes (T1D), the insulin‐producing β cells are destructed by immune mechanisms. It has been hypothesized that the very first immune response in T1D onset comes from innate immune cells, which further activates the adaptive immune cells to attack the islets. Despite intensive research on characterization of islet‐infiltrating immune cells, the kinetics of different immune cells in multiple low‐dose streptozotocin (MLDSTZ)‐induced T1D mouse model is still much unclear. Therefore, we investigated the proportions of innate immune cells such as neutrophils, dendritic cells (DCs), plasmacytoid dendritic cells (pDCs), macrophages, natural killer (NK) cells, and adaptive immune cells (T and B lymphocytes) in thymi, pancreatic‐draining lymph nodes, and spleens of MLDSTZ mice on days 3, 7, 10, and 21 after the first injection of STZ by flow cytometry. The proportions of DCs and B cells were increased from day 3, while the proportions of B‐1a lymphocytes and interferon‐γ+ cells among NK cells were increased, but NK cells were decreased on day 10 in MLDSTZ‐treated mice, illustrating that the initial immune response is induced by DCs and B cells. Later, the proportions of T helper 1 and cytotoxic T cells were increased from day 7, suggesting that the innate immune cells precede adaptive immune cell response in MLDSTZ mice. Altogether, our data demonstrate a possible sequence of events regarding the involvement of DCs, pDCs, NK cells, B‐1a lymphocytes, B, and T cells at the early stage of T1D development.

Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes

“…PHLPP1-KO mice are viable, fertile, and showed no significant differences in basal glycemia, food intake, and body weight compared to WT control mice ( Figures 5 , S5A , and S5B ). We tested whether PHLPP1-KO mice are protected from diabetes progression in the multiple low-dose streptozotocin (MLD-STZ) model of β-cell destruction and diabetes ( Horwitz et al, 2018 ; Luo et al, 2019 ). MLD-STZ for 5 consecutive days induced progressive hyperglycemia and glucose intolerance rendering WT mice overtly diabetic, whereas blood glucose in PHLPP1-KO mice was robustly attenuated ( Figures 4C and 4D ), and glucose tolerance significantly improved at all time points ( Figures 4E and 4F ).…”

Thymulin and peroxiredoxin 6 have protective effects against streptozotocin-induced type 1 diabetes in mice

“…It is known that the cellular response to type 1 diabetes involve heat shock proteins, for example, Hsp90α protein, for which signaling proteins are clients. 20 Next, we evaluated the expression of Hsp90α ( Figure 5 ). In mice with STZ-induced diabetes, a sharp increase in Hsp90α protein expression was observed.…”

Endangered Lymphocytes: The Effects of Alloxan and Streptozotocin on Immune Cells in Type 1 Induced Diabetes

“…Since an immunopathogenic component in T1D had been previously described [36], much attention converged on choosing a model that could better contribute to the study of lymphocytes and their physiology. Although ALX and STZ are the most common pharmacological agents used to induce T1D, many toxicological effects on lymphoid organs and cells have been described [9,10,[37][38][39][40][41][42][43][44]. Both agents were capable of maintaining the animals under T1D conditions during the whole study without causing reversible diabetes or inducing insulin or glucose tolerance effects [45,46].…”