Pancreatic islet inflammation: an emerging role for chemokines
- 1Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
- 2Department of Surgery, Graduate School of Medicine, University of Tennessee Health Science Center, Knoxville, Tennessee, USA
- 3Department of Microbiology, University of Tennessee, Knoxville, Knoxville, Tennessee, USA
- 4Laboratory of Immunogenetics, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
- Correspondence should be addressed to J J Collier; Email: Jason.collier{at}pbrc.edu
-
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 activate cell surface receptors, altering intracellular signaling pathways. 3. Incomplete fatty acid oxidation may also activate signaling pathways, such as NF-κB, 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.
- © 2017 Society for Endocrinology
