Pancreatic islet inflammation: an emerging role for chemokines

Abstract

Both type 1 and type 2 diabetes exhibit features of inflammation associated with alterations in pancreatic islet function and mass. These immunological disruptions, if unresolved, contribute to the overall pathogenesis of disease onset. This review presents the emerging role of pancreatic islet chemokine production as a critical factor regulating immune cell entry into pancreatic tissue as well as an important facilitator of changes in tissue resident leukocyte activity. Signaling through two specific chemokine receptors (i.e., CXCR2 and CXCR3) is presented to illustrate key points regarding ligand-mediated regulation of innate and adaptive immune cell responses. The prospective roles of chemokine ligands and their corresponding chemokine receptors to influence the onset and progression of autoimmune- and obesity-associated forms of diabetes are discussed.

Keywords: chemokine; cytokine; diabetes; inflammation; islet.

Figure 1. Signals that activate NF-κB and STAT1 enhance chemokine production within pancreatic islets that contribute to the inflammatory response influencing both insulin secretion and total β-cell mass

Many signals converge on the NF-κB and STAT1 pathways to coordinately reprogram beta cells at a transcriptional level, leading to inflammation-based changes in insulin secretion, β-cell mass, or both. PRRs can be either cell surface based, such as Toll-like receptor-2 and -4 or positioned intracellularly (e.g., Toll-like receptor-3, NOD1, NOD2, etc.). TNF-α and IL-1 signal through specific cell surface receptors (receptor not shown) and converge on the NF-κB pathway. The interferon family of cytokines signals through cell surface receptors that activate JAK-STAT pathways. Activation of COX2 produces prostaglandins, which may influence leukocyte activity. Cytokine-mediated increases in iNOS elevate intracellular production of nitric oxide, which acts as a rheostat for insulin secretion. COX2: cyclooxygenase-2; IFNs: interferons alpha, beta, and gamma; iNOS: inducible nitric oxide synthase; PRR: pattern recognition receptors.

Figure 2. Conceptual Models for how Obesity may influence Islet Inflammation and Chemokine Production

A. 1. Increased intestinal permeability allows microbial products (e.g., LPS) to enter the circulation. 2. These molecules are “sensed” by pattern recognition receptor enriched in immune cells, such as neutrophils (not shown) and macrophages (shown). An increase in macrophage activation leads to production and release of cytokines (e.g., IL-1β). 3. Distinct pro-inflammatory cytokines (e.g., IL-1β, IFN-γ, TNF-α, etc.) promote transcriptionally active NF-κB and STAT1 proteins. 4. The NF-κB and STAT1 pathways regulate chemokine production in beta-cells; release of β-cell derived chemokines influences innate and adaptive immune responses. B. 1. When consumption of free fatty acids (FFAs) exceeds storage capacity in adipose tissue, these lipids begin to be stored in lean tissues (e.g. liver, muscle, and pancreas). 2. FFAs cell surface receptors, altering intracellular signaling pathways. 3. Incomplete fatty acid oxidation may also activate signaling pathways, such as NF-kB, that are linked with transcriptional changes. 4. Chemokine production is elevated in the obese, insulin resistant state, which would impact both tissue resident and infiltrating leukocytes.

Figure 2. Conceptual Models for how Obesity may influence Islet Inflammation and Chemokine Production

A. 1. Increased intestinal permeability allows microbial products (e.g., LPS) to enter the circulation. 2. These molecules are “sensed” by pattern recognition receptor enriched in immune cells, such as neutrophils (not shown) and macrophages (shown). An increase in macrophage activation leads to production and release of cytokines (e.g., IL-1β). 3. Distinct pro-inflammatory cytokines (e.g., IL-1β, IFN-γ, TNF-α, etc.) promote transcriptionally active NF-κB and STAT1 proteins. 4. The NF-κB and STAT1 pathways regulate chemokine production in beta-cells; release of β-cell derived chemokines influences innate and adaptive immune responses. B. 1. When consumption of free fatty acids (FFAs) exceeds storage capacity in adipose tissue, these lipids begin to be stored in lean tissues (e.g. liver, muscle, and pancreas). 2. FFAs cell surface receptors, altering intracellular signaling pathways. 3. Incomplete fatty acid oxidation may also activate signaling pathways, such as NF-kB, that are linked with transcriptional changes. 4. Chemokine production is elevated in the obese, insulin resistant state, which would impact both tissue resident and infiltrating leukocytes.