Mice lacking beta2-integrin function remain glucose tolerant in spite of insulin resistance, neutrophil infiltration and inflammation

Meakin, P. J., Morrison, V. J. , Sneddon, C. C., Savinko, T., Uotila, L., Jalicy, S. M., Gabriel, J. L., Kang, L., Ashford, M. L.J. and Fagerholm, S. C. (2015) Mice lacking beta2-integrin function remain glucose tolerant in spite of insulin resistance, neutrophil infiltration and inflammation. PLoS ONE, 10(9), e0138872. (doi: 10.1371/journal.pone.0138872) (PMID:26405763) (PMCID:PMC4583187)

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.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.

• Item Type: Articles
• Additional Information: : This work was supported by Biotechnology and Biological Sciences Research Council, Arthritis Research UK, Tenovus Scotland, The Anonymous Trust, the Academy of Finland, Biocentrum Helsinki and the Sigrid Juselius foundation (all to S.C.F) and Diabetes UK and Biotechnology and Biological Sciences Research Council -CASE awards to MLJA. This work was supported in part by a grant from AstraZeneca.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morrison, Dr Vicky
• Authors: Meakin, P. J., Morrison, V. J., Sneddon, C. C., Savinko, T., Uotila, L., Jalicy, S. M., Gabriel, J. L., Kang, L., Ashford, M. L.J., and Fagerholm, S. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2015 Meakin et al.
• First Published: First published in PLoS ONE 10(9): e0138872
• Publisher Policy: Reproduced under a Creative Commons License