Obesity-induced skeletal muscle inflammation is characterized by increased macrophage infiltration and inflammatory cytokine production. In this study, we investigated whether 4-1BB, a member of the TNF receptor superfamily (TNFRSF9) that provides inflammatory signals, participates in obesity-induced skeletal muscle inflammation. Expression of the 4-1BB gene, accompanied by increased levels of inflammatory cytokines, was markedly upregulated in the skeletal muscle of obese mice fed a high-fat diet, in muscle cells treated with obesity factors, and in cocultured muscle cells/macrophages. In vitro stimulation of 4-1BB with agonistic antibody increased inflammatory cytokine levels in TNF -pretreated muscle cells, and this effect was absent in cells derived from 4-1BB-deficient mice. Conversely, disruption of the interaction between 4-1BB and its ligand (4-1BBL) with blocking antibody decreased the release of inflammatory cytokines from cocultured muscle cells/macrophages. Moreover, deficiency of 4-1BB markedly reduced macrophage infiltration and inflammatory cytokine production in the skeletal muscle of mice fed a high-fat diet. These findings indicate that 4-1BB mediates the inflammatory responses in obese skeletal muscle by interacting with its ligand 4-1BBL on macrophages. Therefore, 4-1BB and 4-1BBL may be useful targets for prevention of obesity-induced inflammation in skeletal muscle. 1. Introduction Obesity-induced inflammation, which is commonly observed in major metabolic organs such as adipose tissue, skeletal muscle, and liver, is characterized by increased accumulation of immune cells (macrophages, T cells) and inflammatory cytokine/chemokine production and plays a crucial role in the development of metabolic disorders such as insulin resistance and type 2 diabetes [1, 2]. It is likely that inflammation of skeletal muscle contributes to the diminished fatty acid oxidation and increased insulin resistance [3–7], leading to metabolic complications. Given that skeletal muscle, which constitutes up to 40–50% of body mass, is a major site regulating lipid and glucose metabolism [8], targeting skeletal muscle inflammatory components may be a useful strategy for protecting against obesity-related metabolic disorders. However, the factors involved in obesity-induced skeletal muscle inflammation remain unclear. 4-1BB (tumor necrosis factor receptor superfamily 9, TNFRSF9) is a costimulatory receptor mainly expressed on the surface of activated T cells and natural killer (NK) T cells [9, 10], while its ligand (4-1BBL, TNFSF9) is expressed on
References
[1]
C. N. Lumeng and A. R. Saltiel, “Inflammatory links between obesity and metabolic disease,” Journal of Clinical Investigation, vol. 121, no. 6, pp. 2111–2117, 2011.
[2]
G. S. Hotamisligil, “Inflammation and metabolic disorders,” Nature, vol. 444, no. 7121, pp. 860–867, 2006.
[3]
A. Valerio, A. Cardile, V. Cozzi et al., “TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents,” Journal of Clinical Investigation, vol. 116, no. 10, pp. 2791–2798, 2006.
[4]
K. Tang, P. D. Wagner, and E. C. Breen, “TNF-α-mediated reduction in PGC-1α may impair skeletal muscle function after cigarette smoke exposure,” Journal of Cellular Physiology, vol. 222, no. 2, pp. 320–327, 2010.
[5]
V. Varma, A. Yao-Borengasser, N. Rasouli et al., “Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action,” The American Journal of Physiology, vol. 298, pp. E988–E998, 2009.
[6]
D. Patsouris, P.-P. Li, D. Thapar, J. Chapman, J. M. Olefsky, and J. G. Neels, “Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals,” Cell Metabolism, vol. 8, no. 4, pp. 301–309, 2008.
[7]
T. R. Koves, J. R. Ussher, R. C. Noland et al., “Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance,” Cell Metabolism, vol. 7, no. 1, pp. 45–56, 2008.
[8]
M. Du, X. Yan, J. F. Tong, J. Zhao, and M. J. Zhu, “Maternal obesity, inflammation, and fetal skeletal muscle development,” Biology of Reproduction, vol. 82, no. 1, pp. 4–12, 2010.
[9]
J. C. Hurtado, S. H. Kim, K. E. Pollok, Z. H. Lee, and B. S. Kwon, “Potential role of 4-1BB in T cell activation: comparison with the costimulatory molecule CD28,” Journal of Immunology, vol. 155, no. 7, pp. 3360–3367, 1995.
[10]
D.-H. Kim, W.-S. Chang, Y.-S. Lee et al., “4-1BB engagement costimulates NKT cell activation and exacerbates NKT cell ligand-induced airway hyperresponsiveness and inflammation,” Journal of Immunology, vol. 180, no. 4, pp. 2062–2068, 2008.
[11]
D. S. Vinay and B. S. Kwon, “Role of 4-1BB in immune responses,” Seminars in Immunology, vol. 10, no. 6, pp. 481–489, 1998.
[12]
C. Takahashi, R. S. Mittler, and A. T. Vella, “Cutting edge: 4-1BB is a bona fide CD8 T cell survival signal,” Journal of Immunology, vol. 162, no. 9, pp. 5037–5040, 1999.
[13]
C. T. Y. Cheung, T. A. Deisher, H. Luo et al., “Neutralizing anti-4-1BBL treatment improves cardiac function in viral myocarditis,” Laboratory Investigation, vol. 87, no. 7, pp. 651–661, 2007.
[14]
H. J. Jeon, J.-H. Choi, I.-H. Jung et al., “CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice,” Circulation, vol. 121, no. 9, pp. 1124–1133, 2010.
[15]
Q.-T. Nguyen, S.-A. Ju, S.-M. Park et al., “Blockade of CD137 signaling counteracts polymicrobial sepsis induced by cecal ligation and puncture,” Infection and Immunity, vol. 77, no. 9, pp. 3932–3938, 2009.
[16]
C.-S. Kim, J. G. Kim, B.-J. Lee et al., “Deficiency for costimulatory receptor 4-1BB protects against obesity-induced inflammation and metabolic disorders,” Diabetes, vol. 60, no. 12, pp. 3159–3168, 2011.
[17]
T. H. Tu, C. S. Kim, T. Goto, T. Kawada, B. S. Kim, and R. Yu, “4-1BB/4-1BBL interaction promotes obesity-induced adipose inflammation by triggering bidirectional inflammatory signaling in adipocytes/macrophages,” Mediators of Inflammation, vol. 2012, Article ID 972629, 10 pages, 2012.
[18]
B. S. Kwon, J. C. Hurtado, Z. H. Lee et al., “Immune responses in 4-1BB (CD137)-deficient mice,” Journal of Immunology, vol. 168, no. 11, pp. 5483–5490, 2002.
[19]
W. W. Shuford, K. Klussman, D. D. Tritchler et al., “4-1BB costimulatory signals preferentially induce CD8+T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses,” Journal of Experimental Medicine, vol. 186, no. 1, pp. 47–55, 1997.
[20]
T. A. Rando and H. M. Blau, “Primary mouse myoblast purification, characterization, and transplantation for cell-mediated gene therapy,” Journal of Cell Biology, vol. 125, no. 6, pp. 1275–1287, 1994.
[21]
M. Jové, A. Planavila, R. M. Sánchez, M. Merlos, J. C. Laguna, and M. Vázquez-Carrera, “Palmitate induces tumor necrosis factor-α expression in C2C12 skeletal muscle cells by a mechanism involving protein kinase C and nuclear factor-κB activation,” Endocrinology, vol. 147, no. 1, pp. 552–561, 2006.
[22]
S. Schenk, M. Saberi, and J. M. Olefsky, “Insulin sensitivity: modulation by nutrients and inflammation,” Journal of Clinical Investigation, vol. 118, no. 9, pp. 2992–3002, 2008.
[23]
P. S. Olofsson, L. ？. S？derstr？m, D. W？gs？ter, et al., “CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice,” Circulation, vol. 117, no. 10, pp. 1292–1301, 2008.
[24]
T. Haga, J.-I. Suzuki, H. Kosuge et al., “Attenuation of experimental autoimmune myocarditis by blocking T cell activation through 4-1BB pathway,” Journal of Molecular and Cellular Cardiology, vol. 46, no. 5, pp. 719–727, 2009.
[25]
C. Fiocchi, “Intestinal inflammation: a complex interplay of immune and nonimmune cell interactions,” The American Journal of Physiology, vol. 273, no. 4, pp. G769–G775, 1997.
[26]
M. I. Frisard, R. P. McMillan, J. Marchand et al., “Toll-like receptor 4 modulates skeletal muscle substrate metabolism,” The American Journal of Physiology, vol. 298, no. 5, pp. E988–E998, 2010.
[27]
Y.-P. Li, Y. Chen, J. John et al., “TNF-α acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle,” The FASEB Journal, vol. 19, no. 3, pp. 362–370, 2005.
[28]
B. Kwon, “CD137-CD137 ligand interactions in inflammation,” Immune Network, vol. 9, no. 3, pp. 84–89, 2009.
[29]
D. Drenkard, F. M. Becke, J. Langstein et al., “CD137 is expressed on blood vessel walls at sites of inflammation and enhances monocyte migratory activity,” The FASEB Journal, vol. 21, no. 2, pp. 456–463, 2007.
[30]
H. Schwarz, “Biological activities of reverse signal transduction through CD137 ligand,” Journal of Leukocyte Biology, vol. 77, no. 3, pp. 281–286, 2005.
[31]
H. Lu, D. Huang, R. M. Ransohoff, and L. Zhou, “Acute skeletal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repair,” The FASEB Journal, vol. 25, no. 10, pp. 3344–3355, 2011.
[32]
H. Kanda, S. Tateya, Y. Tamori et al., “MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity,” Journal of Clinical Investigation, vol. 116, no. 6, pp. 1494–1505, 2006.
