Nucleotides released from palmitate challenged muscle cells through pannexin-3 attract monocytes

  1. Amira Klip1,*
  1. 1Program in Cell Biology, the Hospital for Sick Children, Toronto, Ontario, Canada
  2. 2Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark
  3. 3Eli Lilly and Company, Indianapolis, IN, USA
  1. *Corresponding Author: Amira Klip, E-mail: amira{at}sickkids.ca

Abstract

Obesity-associated low-grade inflammation in metabolically relevant tissues contributes to insulin resistance. We recently reported monocyte/macrophage infiltration in mouse and human skeletal muscles. However, the molecular triggers of this infiltration are unknown, and the role of muscle cells in this context is poorly understood.

Animal studies are not amenable to specifically investigate this vectorial cellular communication. Using cell cultures, we investigated the crosstalk between myotubes and monocytes exposed to physiological levels of saturated and unsaturated fatty acids. Media from L6 myotubes treated with palmitate – but not palmitoleate – induced THP1 monocyte migration across transwells. Palmitate activated the TLR4-NFκB pathway in myotubes and elevated cytokine expression, but the monocyte chemoattracting agent was not a polypeptide. Instead, nucleotide degradation eliminated the chemoattracting properties of the myotube conditioned-media. Moreover, palmitate-induced expression and activity of pannexin-3 channels in myotubes was mediated by TLR4-NFkB, and TLR4-NFkB inhibition or pannexin-3 knockdown prevented monocyte chemoattraction. In mice, the expression of pannexin channels increased in adipose tissue and skeletal muscle in response to high fat feeding.

These findings identify pannexins as new targets of saturated fatty acid-induced inflammation in myotubes, and point to nucleotides as possible mediators of immune cell chemoattraction towards muscle in the context of obesity.

  • Received January 28, 2014.
  • Accepted June 3, 2014.

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