Abstract
Beta2-integrins are important in leukocyte trafficking and function, and are regulated through the binding of cytoplasmic proteins, such as kindlin-3, to their intracellular domain. Here, we investigate the involvement of beta2-integrins in the regulation of metabolic disease using mice where the kindlin-3 binding site in the beta2-integrin cytoplasmic tail has been mutated (TTT/AAA-beta2-integrin knock-in (KI) mice), leading to expressed but dysfunctional beta2-integrins and significant neutrophilia in vivo. Beta2-integrin KI mice fed on a high fat diet showed normal weight gain, and normal accumulation of macrophages and lymphocytes in white adipose tissue (WAT) and liver, but increased neutrophil numbers especially in WAT. In addition, beta2-integrin KI mice fed on a high fat diet showed significantly increased peripheral insulin resistance in response to high-fat feeding. However, this was associated with improved glucose disposal following glucose load. Interestingly, beta2-integrin KI neutrophils produced more elastase in vitro, in response to stimulation. Beta2-integrin KI mice displayed variability of tissue inflammatory status, with liver and WAT exhibiting little or no difference in inflammation compared to high fat fed controls, whereas skeletal muscle demonstrated a raised inflammatory profile in association with higher elastase levels and diminished signalling through the IRS1-PKB pathway. In conclusion, although expression of dysfunctional beta2-integrins increased neutrophil production and infiltration into tissue, skeletal muscle was the most affected tissue exhibiting evidence of higher neutrophil activity and insulin resistance. Thus, beta2-integrins modulate glucose homeostasis during high fat feeding predominantly through actions on skeletal muscle to affect metabolic phenotype in vivo.
Highlights
Low-grade chronic inflammation and the increased expression of pro-inflammatory cytokines in adipose tissue, liver and skeletal muscle is associated with insulin resistance in obesity and type 2 diabetes
Leukocyte infiltration and low-grade inflammation is an important component of metabolic dysfunction during high fat feeding, and beta2-integrins are important for leukocyte trafficking and restrict inflammation in various settings in vivo
We have previously reported that disrupting the link between the beta2-integrin and its cytoplasmic regulator, kindlin-3, results in expressed but dysfunctional integrins, leading to reduced T cell trafficking, and to neutrophilia and increased dendritic cell activation and Th1 polarization in vivo [6, 7]
Summary
Low-grade chronic inflammation and the increased expression of pro-inflammatory cytokines in adipose tissue, liver and skeletal muscle is associated with insulin resistance in obesity and type 2 diabetes. In addition to many other leukocyte populations, infiltration of neutrophils and production of the protease elastase by these cells has recently been implicated in the low-grade inflammation in adipose tissue and liver associated with metabolic disease [1, 2]. We have recently reported that mutation of the kindlin-3 binding site in the beta2-integrin intracellular domain results in expressed but dysfunctional integrins in T cells [6]. These mice display increased neutrophil numbers in the bloodstream as well as in the bone marrow, and increased neutrophil survival in vitro [6, 7]. We decided to investigate the role of beta2-integrins in the regulation of leukocyte trafficking, inflammation and metabolic phenotype in high-fat diet fed animals
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