August Krogh Seminar

Crosstalk between muscle cells and immune cells in high fat environments

v/ Dr. Amira Klip, Senior Scientist, The Hospital for Sick Children, and Professor of Paediatrics, Biochemistry and Physiology, The University of Toronto, Canada

Abstract

Obesity-associated low-grade inflammation in metabolically relevant tissues contributes to insulin resistance. We recently reported a noticeable monocyte/macrophage infiltration in mouse and human skeletal muscles, and will present key findings. Further, the molecular triggers of this infiltration are unknown, and recent unpublished findings will be presented. Animal studies are not amenable to specifically investigate the vectorial cellular communication between myocytes and immune cells, but this is discernible using cell culture paradigms. We first investigated the crosstalk between L6 myotubes and monocytes (macrophage precursors) 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 was increased in adipose tissue and skeletal muscle in response to high fat feeding. These findings identify pannexins as a new target 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.

We next investigated if muscle cells affect the polarization status of macrophages. Fatty acid-free media from palmitate-treated muscle cells caused macrophage ‘M1-like’ inflammatory polarization whereas media from palmitoleate-treated muscle cells did not. On their own, palmitate caused macrophage ‘M1-like’ polarization and palmitoleate caused ‘M2-like’ anti-inflammatory polarization. Finally, the converse contribution of macrophages to muscle cells was investigated. Fatty acid-free media from palmitate-treated macrophages conferred insulin resistance to muscle cells, through activation of atypical PKC epsilon and theta in the muscle cells.

These results reveal a bidirectional communication between muscle and immune cells that may underlie the infiltration of macrophages into muscle tissue that occurs in vivo during high fat diets and contributes to the development of insulin resistance.

Key publications for the talk

To be announced.

Research profile

Dr. Amira Klip is a senior scientist in the Cell Biology Program at the SickKids Research Institute and Professor of Paediatrics, Biochemistry, and Physiology at the University of Toronto. In order to understand the process of insulin resistance, a problem for both type 1 and type 2 diabetes, Klip studies insulin action and the cellular and molecular steps involved in this process. She directs a laboratory of ten graduate students/postdoctoral fellows, one technician, and one research associate and works with several pharmaceutical companies to screen and identify modes of action of potential anti-diabetic drugs.

Time

13 May 2014

14:00-15:00: Seminar and discussion
15:00-15:30: Post seminar servings and socializing

Venue

Auditorium 1, August Krogh Building, Universitetsparken 13, DK-2100 Copenhagen

Registration

Participation is free, but please register here.

For PhD students

PhD students participating in August Krogh seminars receive 0,2 ECTS per seminar

Contact

Christian Frøsig, CFrosig@ifi.ku.dk, mobile +45 2875 1617

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