Browsing by Subject "CD18"

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  • Meakin, Paul J.; Morrison, Vicky L.; Sneddon, Claire C.; Savinko, Terhi; Uotila, Liisa; Jalicy, Susan M.; Gabriel, Jennie L.; Kang, Li; Ashford, Michael L. J.; Fagerholm, Susanna C. (2015)
    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.
  • Jahan, Farhana; Madhavan, Sudarrshan; Rolova, Taisia; Viazmina, Larisa; Grönholm, Mikaela; Gahmberg, Carl G. (2018)
    The integrin leukocyte function-associated antigen-1 (LFA-1) plays a pivotal role in leukocyte adhesion and migration, but the mechanism(s) by which this integrin is regulated has remained incompletely understood. LFA-1 integrin activity requires phosphorylation of its 2-chain and interactions of its cytoplasmic tail with various cellular proteins. The -chain is constitutively phosphorylated and necessary for cellular adhesion, but how the -chain regulates adhesion has remained enigmatic. We now show that substitution of the -chain phosphorylation site (S1140A) in T cells inhibits the phosphorylation of the functionally important Thr-758 in the 2-chain, binding of -actinin and 14-3-3 protein, and expression of an integrin-activating epitope after treatment with the stromal cell-derived factor-1. The presence of this substitution resulted in a loss of cell adhesion and directional cell migration. Moreover, LFA-1 activation through the T-cell receptor in cells expressing the S1140A LFA-1 variant resulted in less Thr-758 phosphorylation, -actinin and talin binding, and cell adhesion. The finding that the LFA-1 -chain regulates adhesion through the -chain via specific phosphorylation at Ser-1140 in the -chain has not been previously reported and emphasizes that both chains are involved in the regulation of LFA-1 integrin activity.