Macrophage-Mediated Islet Cell Cytotoxicity in BB Rats

Abstract

Islet cell killing mediated by natural killer cells and T-lymphocytes in diabetes-prone (DP) and diabetic BB rats has been described, but other killing mechanisms may also be involved. Histopathologic studies suggest that macrophages are the first immune cells to infiltrate islets. To determine if macrophages are the first cells mediating islet damage, macrophagemediated cytotoxicity was evaluated in BB rats of different ages. Splenic macrophages isolated from DP rats at 33,100,120, and 140 days of age showed no enhanced islet killing compared with diabetes-resistant rats. Killing at diabetes onset (121 ± 14 days) was markedly increased (43 ± 9.3%) compared with agematched diabetes-resistant controls (19 ± 8.3%, P < .001). Islet inflammation was monitored at all time points. At 120 and 140 days of age, 9 of 11 (82%) DP rats had insulitis, and cytotoxicity was increased in 6 of 11 (55%) rats, which is similar to the number of DP rats that progress to diabetes. At 100 days, 3 of 6 (50%) DP rats again showed diabetic levels of killing, even in the absence of insulitis. These data indicate that 1) islet inflammation is dissociated from clinical diabetes onset, 2) splenic macrophages may have islet-killing potential before islet inflammation, 3) macrophage-mediated islet killing is elevated in all animals immediately after diabetes onset, and 4) macrophages, in addition to natural killer cells and T-lymphocytes, are responsible for cell-mediated islet destruction and thus are candidates for the first cellular effector to result in islet killing. Diabetes 38:1329-31,1989

Quantitative phenotypic and functional analyses of islet immune cells before and after diabetes onset in the BB rat

“…This to some extent may also explain the lack of MHC restriction on islet cytolytic events. Our functional data are consistent with those non-restricted cytolytic data observed using spleen effector cells in previous studies [24,25]. This killing is unlikely to be alloreactivity since similar results are obtained using Wistar Furth or DP islet target cells.…”

“…This killing is unlikely to be alloreactivity since similar results are obtained using Wistar Furth or DP islet target cells. Our previously reported data of non-restricted splenic derived macrophage-mediated islet cytolysis could be related to total islet effector cell killing reported herein [24]. These data do not indicate which cell subtype(s) is (are) the major islet effector cell.…”

Redox-Sensitive Innate Immune Pathways During Macrophage Activation in Type 1 Diabetes

“…Similar to the NOD mouse, macrophage-depleting silica treatment of DP-BB rats almost completely abrogates onset of spontaneous T1D (142). In addition, tracking the immune infiltration throughout disease progression revealed that macrophages are the initial infiltrating immune cells into the islets of DP-BB rats (65,102,209), and that macrophages can also play an effector role during the autoimmune attack (95,99,132). In addition to murine models of autoimmune diabetes, histological analyses of pancreata sections from patients with T1D have also demonstrated an influx in macrophage recruitment into the islets (66,79,82,165).…”

4-Octyl itaconate attenuates glycemic deterioration by regulating macrophage polarization in mouse models of type 1 diabetes

“…The autoimmune response triggering type 1 diabetes relies on the crosstalk between pancreatic beta cells and the immune system. Histology insulitis results obtained from experimental models of type 1 diabetes and type 1 diabetes patients demonstrate that macrophages and dendritic cells are the first cells that infiltrate into the islets (Nagy et al 1989;Dahlén et al 1998;Jörns et al 2014;Walker et al 1988;Hanenberg et al 1989). Macrophage polarization is defined into two broad subsets: the classically activated M1 macrophages and alternatively activated M2 macrophages.…”