Big Mac Attack: Does It Play a Direct Role for Monocytes/Macrophages in Type 1 Diabetes?

Type 1 diabetes is conventionally thought to result from T-cell–mediated autoimmune destruction of pancreatic -cells (1–3). Experimental and clinical evidence accumulated over the past two decades indicates that T-cells play a critical role in the pathogenesis of type 1 diabetes in both humans and the nonobese diabetic (NOD) mouse model of this disease (4). Indeed, the important contribution of T-cells toward the pathogenesis of type 1 diabetes has been supported not only by a variety of physiologic and histological studies but, in addition, through a number of immunotherapeuticbased studies involving selective targeting of T-cells (4,5). More recently, it has been shown that B-cells also play an important role in type 1 diabetes development (6), since NOD mice deficient in these cells do not develop insulitis or overt diabetes (7), and that the depletion of B-cells with anti-CD20 antibody prevents disease (8). Apart from diabetogenic Tand B-cells, emerging evidence suggests that macrophages are involved in the final stage of autoimmune-mediated -cell destruction (9,10). For example, after monocyte depletion, passively transferred diabetogenic T-cells fail to induce diabetes, and activated macrophages can directly kill -cells in vitro (10). However, direct evidence that activated monocytes/ macrophages kill -cells is minimal or lacking, depending on one’s perspective. In the current issue of Diabetes, Martin et al. (11), using multiple transgenic mouse models, provide convincing evidence that monocytes can be recruited to pancreatic islets when the chemokine CCL2 is expressed transgenically in -cells and that these immune system cells are capable of destroying -cells, resulting in diabetes in the absence of mature Tand B-cells. Therefore, this observation adds monocytes/macrophages to the growing list of immune cells involved in islet cell destruction in type 1 diabetes. There are two distinct phases for autoimmune-mediated diabetes: insulitis and diabetes. In the early stages of insulitis, mixed leukocytes including activated macrophages, B-cells, T-cells, and NK cells are attracted to the islets by chemokines. Chemokines are chemoattractant proteins (12,13) produced by cells in response to infection or cell damage (13). Leukocytes, such as lymphocytes, monocytes, and NK cells, expressing the appropriate receptors, migrate toward the source of chemokine production. Chemokines are subdivided into four subfamilies (C, CC, CXC, and CX3C) based on the location of the first conserved NH2-terminal cysteine residues (13). The largest group is the CC family, where two cysteine residues are immediately adjacent to each other. CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a CC chemokine produced by lymphocytes, monocytes, endothelial cells, and other cells in response to inflammatory stimuli (14). Through its receptor CCR2, MCP-1/CCL2 potently attracts monocytes, Tcells, and NK cells. Although MCP-1 is expressed in normal human and rodent islets (15), transgenic mice overexpressing MCP-1 under control of the insulin promoter develop an intense insulitis, but overt diabetes was not seen in early studies (16). The temporal pattern of MCP-1 and other chemokine expression correlates with the progression of insulitis and -cell destruction in NOD mice (17). Despite substantial indirect evidence that CCL2 is involved in the pathogenesis of type 1 diabetes, its precise role in the development of insulitis and islet cell destruction is incompletely understood. Martin et al. (11) add to the accumulating evidence that CCL2 production and numbers of circulating monocytes play a more important role in the onset of diabetes than was previously suspected. The investigators demonstrate that monocytes/macrophages are recruited in a concentration-dependent manner to the islets by transgenic expression of CCL2 in -cells under the control of the insulin promoter. The CCL2mediated monocyte recruitment requires the CCL2 receptor (CCR2), since deletion of CCR2 in RIPCCL2 mice abolishes homing to the islets. Strikingly, and in contrast to previous studies (16,18), transgenic mice displaying high MCP-1 expression and serum MCP-1 levels not only develop insulitis but also go on to islet cell destruction and clinical diabetes. The explanation for this apparent discrepancy may lie both in the relatively high level of MCP-1 expressed (up to 1.4 ng/ml in the serum) and in the fact that MCP-1 production in the Martin et al. (11) study was restricted to islets, whereas expression was more widespread in the study of Rutledge et al. (18). Importantly, to assess the influence of Tand B-cells, Martin et al. bred the RIPCCL2 transgene onto a Rag-1 / background to generate mice expressing CCL2 in -cells in the absence of mature Tand B-cells. Remarkably, the hybrid mice developed diabetes with a similar time course to that of immunocompetent Rag1 / controls. Thus, although diabetogenic Tand B-cells may be central to the pathogenesis of type 1 diabetes under “physiological” conditions (2,19), the Martin et al. study extends data from several other laboratories (9,10,16,20), suggesting that monocytes/macrophages also may play a critical role. Most current therapies, such as the induction From the Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida. Corresponding author: Li-Jun Yang, [email protected]. DOI: 10.2337/db08-1007 © 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 3025. COMMENTARY