Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation

Abstract

Pancreatic islets produce and secrete cytokines and chemokines in response to inflammatory and metabolic stress. The physiological role of these “isletokines” in health and disease is largely unknown. We observed that islets release multiple inflammatory mediators in patients undergoing islet transplants within hours of infusion. The proinflammatory cytokine interferon-γ–induced protein 10 (IP-10/CXCL10) was among the highest released, and high levels correlated with poor islet transplant outcomes. Transgenic mouse studies confirmed that donor islet–specific expression of IP-10 contributed to islet inflammation and loss of β-cell function in islet grafts. The effects of islet-derived IP-10 could be blocked by treatment of donor islets and recipient mice with anti–IP-10 neutralizing monoclonal antibody. In vitro studies showed induction of the IP-10 gene was mediated by calcineurin-dependent NFAT signaling in pancreatic β-cells in response to oxidative or inflammatory stress. Sustained association of NFAT and p300 histone acetyltransferase with the IP-10 gene required p38 and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) activity, which differentially regulated IP-10 expression and subsequent protein release. Overall, these findings elucidate an NFAT-MAPK signaling paradigm for induction of isletokine expression in β-cells and reveal IP-10 as a primary therapeutic target to prevent β-cell–induced inflammatory loss of graft function after islet cell transplantation.

A20 as an immune tolerance factor can determine islet transplant outcomes

“…CXCL10 has been demonstrated to promote immune infiltration and destruction of islets in autoimmune models (37), and it is highly expressed in insulitic lesions in patients with recent-onset T1D (52). Beyond this, CXCL10 promotes immune infiltration in islet isografts (53) and allografts (38,54), and is linked to poor clinical islet transplant outcomes (9,55). Suppression of CXCL10 is significant as neutralization of CXCL10 can prolong graft survival in our model.…”

Targeting Acute Islet Inflammation to Preserve Graft Mass and Long-Term Function

“…Originally, it was assumed that infiltrating immune cells were sole producers of proinflammatory cytokines in islets. However, flow cytometry, immunohistochemistry, and laser capture analysis studies revealed that the islet endocrine cells also produce proinflammatory mediators that can elicit immune cell responses [47][48][49][50][51][52][53][54][55]. In fact, the islet cells produce and release dozens of isletokines that can be detected in the blood circulation upon infusion that correlate with transplant outcomes [55,56].…”

“…However, flow cytometry, immunohistochemistry, and laser capture analysis studies revealed that the islet endocrine cells also produce proinflammatory mediators that can elicit immune cell responses [47][48][49][50][51][52][53][54][55]. In fact, the islet cells produce and release dozens of isletokines that can be detected in the blood circulation upon infusion that correlate with transplant outcomes [55,56]. In particular, HMGB1, MCP-1 and IP-10 are highly expressed and released in damaged or stressed islets and play a key role in initiating acute inflammation in transplanted islets [55,[57][58][59][60][61][62].…”

“…In fact, the islet cells produce and release dozens of isletokines that can be detected in the blood circulation upon infusion that correlate with transplant outcomes [55,56]. In particular, HMGB1, MCP-1 and IP-10 are highly expressed and released in damaged or stressed islets and play a key role in initiating acute inflammation in transplanted islets [55,[57][58][59][60][61][62].…”

“…Double blockade by both etanercept and anakinra improves the response [96]. There is also strong evidence to suggest that chemokines MCP-1 and IP-10 play key roles in initiating inflammatory responses in islet transplantation [55,57]. It should also be noted that IP-10 is a key isletokine expressed by beta cells in insulitic lesions in type 1 diabetes [97][98][99].…”