title: Nucleotides released from palmitate-challenged muscle cells through pannexin-3 attract monocytes.
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 the specific investigation of 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 Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) 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 were mediated by TLR4-NF-κB, and TLR4-NF-κB 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 toward muscle in the context of obesity.
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Pillon
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Yujin E
authors.initials: YE
authors.lastname: Li
authors.affiliation: Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Lisbeth N
authors.initials: LN
authors.lastname: Fink
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Brozinick
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nikolayev
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Ming-Shang
authors.initials: MS
authors.lastname: Kuo
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Bilan
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada amira@sickkids.ca.
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
mesh_terms: D000818:Animals; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D017630:Connexins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009711:Nucleotides; C492765:PANX2 protein, human; D010168:Palmitates; C503631:Panx1 protein, mouse; D051197:Toll-Like Receptor 4; C528477:pannexin 3 protein, mouse