The p75 Neurotrophin Receptor Is Required for the Major Loss of Sympathetic Nerves From Islets Under Autoimmune Attack

Abstract

Our goal was to determine the role of the p75 neurotrophin receptor (p75NTR) in the loss of islet sympathetic nerves that occurs during the autoimmune attack of the islet. The islets of transgenic (Tg) mice in which β-cells express a viral glycoprotein (GP) under the control of the insulin promotor (Ins2) were stained for neuropeptide Y before, during, and after virally induced autoimmune attack of the islet. Ins2-GPTg mice injected with lymphocytic choriomeningitis virus (LCMV) lost islet sympathetic nerves before diabetes development but coincident with the lymphocytic infiltration of the islet. The nerve loss wasmarked and islet-selective. Similar nerve loss, chemically induced, was sufficient to impair sympathetically mediated glucagon secretion. In contrast, LCMV-injected Ins2-GPTg mice lacking the p75NTR retained most of their islet sympathetic nerves, despite both lymphocytic infiltration and development of diabetes indistinguishable from that of p75NTR wild-type mice. We conclude that an nducible autoimmune attack of the islet causes a marked and islet-selective loss of sympathetic nerves that precedes islet collapse and hyperglycemia. The p75NTR mediates this nerve loss but plays no role in mediating the loss of islet β-cells or the subsequent diabetes. p75NTR-mediated nerve loss may contribute to the impaired glucose counterregulation seen in type 1 diabetes.

Early sympathetic islet neuropathy in autoimmune diabetes: lessons learned and opportunities for investigation

“…A more recently developed non-viral method of diabetes induction involves the administration of multiple, sequential, pharmacological agents which induce in the RIP-GP mouse immunological responses similar to those seen during the viral attack [21]. The loss of islet sympathetic nerves is approximately 80% using the viral method [22] and 60% using the non-viral method (Fig. 1).…”

“…Even before diabetes onset, the minority of NOD islets that are heavily infiltrated have fewer sympathetic nerves than the majority of islets which are only sparsely infiltrated [20]. Likewise, in the RIP-GP mouse, there is no loss of islet sympathetic nerves before the islet is infiltrated, yet there is a major loss as soon as the islet becomes heavily infiltrated [22]. The implication of these correlational studies was confirmed by an interventional study: blocking the lymphocytic infiltration of the islet by the administration of complete Freund’s adjuvant to NOD mice prevented the loss of islet sympathetic nerves as well as the development of diabetes [20].…”

“…Fortunately, the differing time courses and magnitudes of infiltration found in the various animal models of autoimmune diabetes have answered this question. In the BB rat [19], NOD mouse [20] and RIP-GP mouse [22] islet nerve loss is observed within 1–2 weeks of diabetes onset, suggesting an active and rapid pruning of islet sympathetic nerves. Importantly, in human type 1 diabetes, loss of islet sympathetic nerves has also been demonstrated 1–2 weeks after diabetes onset [23].…”

“…Subsequently, the predictable timing of islet infiltration offered by the inducible diabetes of the RIP-GP mouse has proved to be instrumental in identifying exactly when islet sympathetic nerves are lost. Four days after LCMV injection neither infiltration nor nerve loss is observed in the islets of these mice [22]. However, seven days after LCMV injection there is a marked infiltration of the islet accompanied by marked loss of islet sympathetic nerves [22] despite the fact that diabetic hyperglycaemia does not appear until two days later.…”

“…Four days after LCMV injection neither infiltration nor nerve loss is observed in the islets of these mice [22]. However, seven days after LCMV injection there is a marked infiltration of the islet accompanied by marked loss of islet sympathetic nerves [22] despite the fact that diabetic hyperglycaemia does not appear until two days later. Thus, we conclude from these studies that islet sympathetic nerves are destroyed coincident with islet infiltration and that by the time enough beta cells are destroyed to produce hyperglycaemia a majority of islet sympathetic nerves have already been lost.…”