Pancreatic β‐Cell production of CXCR3 ligands precedes diabetes onset

Abstract

Type 1 diabetes mellitus (T1DM) results from immune cell-mediated reductions in function and mass of the insulin-producing β-cells within the pancreatic islets. While the initial trigger(s) that initiates the autoimmune process is unknown, there is a leukocytic infiltration that precedes islet β-cell death and dysfunction. Herein, we demonstrate that genes encoding the chemokines CXCL9, 10, and 11 are primary response genes in pancreatic β-cells and are also elevated as part of the inflammatory response in mouse, rat, and human islets. We further established that STAT1 participates in the transcriptional control of these genes in response to the pro-inflammatory cytokines IL-1β and IFN-γ. STAT1 is phosphorylated within five minutes after β-cell exposure to IFN-γ, with subsequent occupancy at proximal and distal response elements within the Cxcl9 and Cxcl11 gene promoters. This increase in STAT1 binding is coupled to the rapid appearance of chemokine transcript. Moreover, circulating levels of chemokines that activate CXCR3 are elevated in non-obese diabetic (NOD) mice, consistent with clinical findings in human diabetes. We also report herein that mice with genetic deletion of CXCR3 (receptor for ligands CXCL9, 10, and 11) exhibit a delay in diabetes development after being injected with multiple low doses of streptozotocin. Therefore, we conclude that production of CXCL9, 10, and 11 from islet β-cells controls leukocyte migration and activity into pancreatic tissue, which ultimately influences islet β-cell mass and function.

Pancreatic islet inflammation: an emerging role for chemokines

“…Sixth, there are defects in insulin secretion and calcium usage in rodent and human islets associated with T1D and T2D (Boucher, et al 2004; Burke et al 2015b; Do, et al 2014; Dula, et al 2010; Kenty and Melton 2015; Qureshi, et al 2015; Ramadan, et al 2011). Seventh, immune cells infiltrate the islets in both T1D and T2D (Boni-Schnetzler, et al 2008; Burke, et al 2016; Ehses, et al 2007; Gepts 1965; Richardson, et al 2009; Willcox, et al 2009). With this last point in mind, we note that excellent reviews exist discussing the immunology of diabetes (Boldison and Wong 2016; Castano and Eisenbarth 1990; Wallberg and Cooke 2013).…”

“…These two receptors are also important because they exemplify enriched expression in neutrophils (CXCR2) and T-cells (CXCR3). Because β-cell exposure to inflammatory mediators induces various chemokine ligands that bind to CXCR2 and CXCR3 (Burke et al 2016; Burke, et al 2015a; Burke, et al 2014; Burke et al 2015b), we discuss what is known about the activation pathways of these two receptors and the downstream effector mechanisms that contribute to immune activation and subsequent β cell destruction.…”

“…Serum CXCL10 levels are increased in both human subjects and in the NOD mouse model, linking elevated chemokine production with diabetes (Antonelli, et al 2014; Christen, et al 2003; Corrado et al 2014). When CXCR3 is knocked out, there is a delay in the onset of virally induced diabetes (Frigerio, et al 2002) and in diabetes induced by multiple low doses of streptozotocin (Burke et al 2016). By contrast, when CXCR3 null mice are crossed onto the NOD background, TID development is accelerated (Yamada, et al 2012).…”

“…Blocking CXCL10 activity with neutralizing antibodies prevented re-infiltration of pancreatic islets after a course of anti-CD3 therapy (Lasch, et al 2015). Because T-cells primed with autoantigens typically produce and secrete IFN-γ, targeted upregulation of CXCL10 by IFN-γ signaling in β-cells is likely contributing to T1D disease pathology (Burke, et al 2013a; Burke et al 2016; Lundberg, et al 2016). The enhanced transcription of the CXCL10 gene is also consistent with heightened STAT1 activity in islet β-cells (Burke et al 2013a; Lundberg et al 2016).…”

“…increase the expression of CXCL9 and CXCL11 in mouse, rat, and human β-cells using activated STAT1 as a key component of the signaling response (Burke et al 2016). STAT1 is therefore a key driver of chemokine production (Burke et al 2013a; Burke et al 2016) and inducible nitric oxide synthase abundance and activity (Burke et al 2015b; Burke, et al 2013b; Corbett, et al 1993; Corbett, et al 1992; Heitmeier, et al 1997). Increased STAT1 expression is also strongly correlated with HLA class I (i.e.…”