View Item 

Show simple item record

Palmitate‐TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing

dc.contributor.authorDavis, Frank M.
dc.contributor.authordenDekker, Aaron
dc.contributor.authorJoshi, Amrita D.
dc.contributor.authorWolf, Sonya J.
dc.contributor.authorAudu, Christopher
dc.contributor.authorMelvin, William J.
dc.contributor.authorMangum, Kevin
dc.contributor.authorRiordan, Mary O.
dc.contributor.authorKunkel, Steven L.
dc.contributor.authorGallagher, Katherine A.
dc.date.accessioned2021-01-05T18:46:46Z
dc.date.availableWITHHELD_12_MONTHS
dc.date.available2021-01-05T18:46:46Z
dc.date.issued2020-12
dc.identifier.citationDavis, Frank M.; denDekker, Aaron; Joshi, Amrita D.; Wolf, Sonya J.; Audu, Christopher; Melvin, William J.; Mangum, Kevin; Riordan, Mary O.; Kunkel, Steven L.; Gallagher, Katherine A. (2020). "Palmitate‐TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing." European Journal of Immunology 50(12): 1929-1940.
dc.identifier.issn0014-2980
dc.identifier.issn1521-4141
dc.identifier.urihttps://hdl.handle.net/2027.42/163876
dc.description.abstractChronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte‐macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB‐mediated inflammatory gene promoters driving macrophage‐mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate‐induced Jmjd3 expression is controlled via TLR4/MyD88‐dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4−/−) or MyD88 (MyD88−/−) negated the palmitate‐induced changes in Jmjd3 and downstream NFκB‐induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK‐J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3‐mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor‐based therapy may represent a novel treatment for nonhealing diabetic wounds.Palmitate drives chronic macrophage mediated inflammation in diabetic tissue via upregulation of the histone demethylase, Jmjd3, and a histone demethylase inhibitor‐based therapy may represent a novel treatment for non∖healing diabetic wounds.
dc.publisherWiley Periodicals, Inc.
dc.subject.otherEpigenetics
dc.subject.otherDiabetes
dc.subject.otherToll‐like receptor
dc.subject.otherMacrophage
dc.subject.otherWound
dc.titlePalmitate‐TLR4 signaling regulates the histone demethylase, JMJD3, in macrophages and impairs diabetic wound healing
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelBiological Chemistry
dc.subject.hlbsecondlevelPublic Health
dc.subject.hlbtoplevelHealth Sciences
dc.subject.hlbtoplevelScience
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/163876/1/eji4870.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/163876/2/eji4870-sup-0001-SuppMat.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/163876/3/eji4870_am.pdf
dc.identifier.doi10.1002/eji.202048651
dc.identifier.sourceEuropean Journal of Immunology
dc.identifier.citedreferenceWegner, M., Neddermann, D., Piorunska‐Stolzmann, M. and Jagodzinski, P. P. Role of epigenetic mechanisms in the development of chronic complications of diabetes. Diabetes Res. Clin. Pract. 2014. 105: 164 – 175.
dc.identifier.citedreferenceRay, I., Mahata, S. K. and De, R. K. Obesity: an immunometabolic perspective. Front. Endocrinol. (Lausanne). 2016. 7: 157.
dc.identifier.citedreferenceShi, H., Kokoeva, M V., Inouye, K., Tzameli, I., Yin, H. and Flier, J S. TLR4 links innate immunity and fatty acid‐induced insulin resistance. J. Clin. Invest. 2006. 116: 3015 – 3025.
dc.identifier.citedreferenceFalanga, V. Wound healing and its impairment in the diabetic foot. Lancet (London, England). 2005. 366: 1736 – 1743.
dc.identifier.citedreferenceMirza, R. E., Fang, M. M., Ennis, W. J. and Koh, T. J. Blocking interleukin‐1 induces a healing‐associated wound macrophage phenotype and improves healing in type 2 diabetes. Diabetes. 2013. 62: 2579 – 2587.
dc.identifier.citedreferenceMirza, R. E., Fang, M. M., Weinheimer‐Haus, E. M., Ennis, W. J. and Koh, T. J. Sustained inflammasome activity in macrophages impairs wound healing in type 2 diabetic humans and mice. Diabetes. 2014. 63: 1103 – 1114.
dc.identifier.citedreferenceMirza, R. E., Fang, M. M., Novak, M. L., Urao, N., Sui, A., Ennis, W. J. and Koh, T. J. Macrophage PPARγ and impaired wound healing in type 2 diabetes. J. Pathol. 2015. 236: 433 – 444.
dc.identifier.citedreferenceHuang, S., Rutkowsky, J. M., Snodgrass, R. G., Ono‐Moore, K. D., Schneider, D. A., Newman, J. W., Adams, S. H. et al., Saturated fatty acids activate TLR‐mediated proinflammatory signaling pathways. J. Lipid Res. 2012. 53: 2002 – 2013.
dc.identifier.citedreferenceNagareddy, P. R., Kraakman, M., Masters, S. L., Stirzaker, R. A., Gorman, D. J., Grant, R. W., Dragoljevic, D. et al., Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 2014. 19: 821 – 835.
dc.identifier.citedreferenceOsborn, O., Olefsky, J M. The cellular and signaling networks linOsborn, O., Olefsky, J. M. The cellular and signaling networks linking the immune system and metabolism in disease. Nature Medicine 2012. 18 ( 3 ): 363 – 374. https://doi.org/10.1038/nm.2627king
dc.identifier.citedreferenceDavis, F. M., denDekker, A., Kimball, A., Joshi, A. D., El Azzouny, M., Wolf, S. J., Obi, A. T. et al., Epigenetic regulation of TLR4 in diabetic macrophages modulates immunometabolism and wound repair. J. Immunol. 2020. 204: 2503 – 2513.
dc.identifier.citedreferenceEdwards, T. M. and Myers, J. P. Environmental exposures and gene regulation in disease etiology. Environ. Health Perspect. 2007. 115: 1264 – 1270.
dc.identifier.citedreferenceSkinner, M. K., Manikkam, M. and Guerrero‐Bosagna, C. Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol. Metab. 2010. 21: 214 – 222.
dc.identifier.citedreferenceKumar, S., Pamulapati, H. and Tikoo, K. Fatty acid induced metabolic memory involves alterations in renal histone H3K36me2 and H3K27me3. Mol Cell Endocrinol. 2016. 422: 233 – 242.
dc.identifier.citedreferenceZhong, Q. and Kowluru, R A. Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon. J. Cell. Biochem. 2010. 110: 1306 – 1313.
dc.identifier.citedreferenceTogliatto, G., Dentelli, P. and Brizzi, M. F. Skewed epigenetics: An alternative therapeutic option for diabetes complications. J. Diabetes Res. 2015. 2015: 373708.
dc.identifier.citedreferenceDavis, F., Kimball, A., Boniakowski, A. and Gallagher, K. Dysfunctional wound healing in diabetic foot ulcers: New crossroads. Curr. Diab. Rep. 2018. 18: 2.
dc.identifier.citedreferenceLochmann, T. L., Powell, K. M., Ham, J., Floros, K. V., Heisey, D. A. R., Kurupi, R. I. J., Calbert, M. L. et al., Targeted inhibition of histone H3K27 demethylation is effective in high‐risk neuroblastoma. Sci. Transl. Med. 2018. 10.
dc.identifier.citedreferenceTaylor, K. R., Trowbridge, J. M., Rudisill, J. A., Termeer, C. C., Simon, J. C. and Gallo, R. L. Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J. Biol. Chem. 2004. 279: 17079 – 17084.
dc.identifier.citedreferenceAsea, A., Rehli, M., Kabingu, E., Boch, J. A., Baré, O., Auron, P. E., Stevenson, M. A. et al., Novel signal transduction pathway utilized by extracellular HSP70. Role of toll‐like receptor (TLR) 2 and TLR4. J. Biol. Chem. 2002. 277: 15028 – 15034.
dc.identifier.citedreferenceWang, X., Cao, Q., Yu, L., Shi, H., Xue, B. and Shi, H. Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity. JCI Insight. 2016. 1: e87748.
dc.identifier.citedreferenceEl‐Osta, A., Brasacchio, D., Yao, D., Pocai, A., Jones, P. L., Roeder, R. G., Cooper, M. E. et al., Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J. Exp. Med. 2008. 205: 2409 – 2417.
dc.identifier.citedreferenceParathath, S., Grauer, L., Huang, L. ‐. S., Sanson, M., Distel, E., Goldberg, I. J. and Fisher, E. A. Diabetes adversely affects macrophages during atherosclerotic plaque regression in mice. Diabetes. 2011. 60: 1759 – 1769.
dc.identifier.citedreferenceReddy, M. A., Zhang, E. and Natarajan, R. Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia. 2015. 58: 443 – 455.
dc.identifier.citedreferenceMancuso, G., Midiri, A., Beninati, C., Piraino, G., Valenti, A., Nicocia, G., Teti, D. et al., Mitogen‐activated protein kinases and NF‐kappa B are involved in TNF‐alpha responses to group B streptococci. J. Immunol. 2002. 169: 1401 – 1409.
dc.identifier.citedreferenceLoffreda, S., Yang, S. Q., Lin, H. Z., Karp, C. L., Brengman, M. L., Wang, D. J., Klein, A. S. et al., Leptin regulates proinflammatory immune responses. FASEB J. 1998. 12: 57 – 65.
dc.identifier.citedreferenceParekh, P. I., Petro, A. E., Tiller, J. M., Feinglos, M. N. and Surwit, R. S. Reversal of diet‐induced obesity and diabetes in C57BL/6J mice. Metabolism. 1998. 47: 1089 – 1096.
dc.identifier.citedreferenceRiera‐Borrull, M., Cuevas, V. D., Alonso, B., Vega, M. A., Joven, J., Izquierdo, E. and ÁL, C. Palmitate conditions macrophages for enhanced responses toward inflammatory stimuli via JNK activation. J. Immunol. 2017. 199: 3858 – 3869.
dc.identifier.citedreferenceWang, Y., Qian, Y., Fang, Q., Zhong, P., Li, W., Wang, L., Fu, W. et al., Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2. Nat. Commun. 2017. 8: 13997.
dc.identifier.citedreferenceAhmad, R., Al‐Roub, A., Kochumon, S., Akther, N., Thomas, R., Kumari, M., Koshy, M. S. et al., The synergy between palmitate and TNF‐α for CCL2 production is dependent on the TRIF/IRF3 pathway: Implications for metabolic inflammation. J. Immunol. 2018. 200: 3599 – 3611.
dc.identifier.citedreferenceIshii, M., Wen, H., Corsa, C. A. S., Liu, T., Coelho, A. L., Allen, R. M., Carson, W. F. et al., Epigenetic regulation of the alternatively activated macrophage phenotype. Blood. 2009. 114: 3244 – 3254.
dc.identifier.citedreferenceCaesar, R., Tremaroli, V., Kovatcheva‐Datchary, P., Cani, P. D. and Bäckhed, F. Crosstalk between gut microbiota and dietary lipids aggravates WAT inflammation through TLR signaling. Cell Metab. 2015. 22: 658 – 668.
dc.identifier.citedreferenceJia, L., Vianna, C. R., Fukuda, M., Berglund, E. D., Liu, C., Tao, C., Sun, K. et al., Hepatocyte Toll‐like receptor 4 regulates obesity‐induced inflammation and insulin resistance. Nat. Commun. 2014. 5: 3878.
dc.identifier.citedreferenceGallagher, K. A., Joshi, A., Carson, W. F., Schaller, M., Allen, R., Mukerjee, S., Kittan, N. et al., Epigenetic changes in bone marrow progenitor cells influence the inflammatory phenotype and alter wound healing in type 2 diabetes. Diabetes. 2015. 64: 1420 – 1430.
dc.identifier.citedreferenceSmith, K. B. and Smith, M S. Obesity statistics. Prim. Care ‐ Clin. Off. Pract. 2016. 43: 121 – 135.
dc.identifier.citedreferenceKruidenier, L., Chung, C., Cheng, Z., Liddle, J., Che, K., Joberty, G., Bantscheff, M. et al., A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012. 488: 404 – 408.
dc.identifier.citedreferenceMartinez, F. O., Helming, L. and Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 2009. 27: 451 – 483.
dc.identifier.citedreferenceMartinez, F. O., Sica, A., Mantovani, A. and Locati, M. Macrophage activation and polarization. Front. Biosci. 2008. 13: 453 – 461.
dc.identifier.citedreferenceLumeng, C. N., DeYoung, S. M., Bodzin, J. L. and Saltiel, A. R. Increased inflammatory properties of adipose tissue macrophages recruited during diet‐induced obesity. Diabetes. 2007. 56: 16 – 23.
dc.identifier.citedreferenceWood, S., Jayaraman, V., Huelsmann, E. J., Bonish, B., Burgad, D., Sivaramakrishnan, G., Qin, S. et al., Pro‐inflammatory chemokine CCL2 (MCP‐1) promotes healing in diabetic wounds by restoring the macrophage response. Liu G, ed. PLoS One. 2014. 9: e91574.
dc.identifier.citedreferenceWeisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L. and Ferrante, A. W. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 2003. 112: 1796 – 808.
dc.identifier.citedreferenceHewagama, A. and Richardson, B. The genetics and epigenetics of autoimmune diseases. J. Autoimmun. 2009. 33: 3 – 11.
dc.identifier.citedreferenceJaenisch, R. and Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 2003. 33: 245 – 254.
dc.identifier.citedreferenceKimball, A. S., Joshi, A., Carson, W. F., Boniakowski, A. E., Schaller, M., Allen, R., Bermick, J. et al., The histone methyltransferase MLL1 directs macrophage‐mediated inflammation in wound healing and is altered in a murine model of obesity and type 2 diabetes. Diabetes. 2017. 66: 2459 – 2471.
dc.identifier.citedreferenceSchlesinger, Y., Straussman, R., Keshet, I., Farkash, S., Hecht, M., Zimmerman, J., Eden, E. et al., Polycomb‐mediated methylation on Lys27 of histone H3 pre‐marks genes for de novo methylation in cancer. Nat. Genet. 2007. 39: 232 – 236.
dc.identifier.citedreferenceLee, J. Y., Sohn, K. H., Rhee, S. H. and Hwang, D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase‐2 mediated through toll‐like receptor 4. J. Biol. Chem. 2001. 276: 16683 – 16689.
dc.identifier.citedreferenceWeigert, C., Brodbeck, K., Staiger, H., Kausch, C., Machicao, F., Häring, H. U. and Schleicher, E. D. Palmitate, but not unsaturated fatty acids, induces the expression of interleukin‐6 in human myotubes through proteasome‐dependent activation of nuclear factor‐kappaB. J. Biol. Chem. 2004. 279: 23942 – 23952.
dc.identifier.citedreferenceLancaster, G. I., Langley, K. G., Berglund, N. A., Kammoun, H. L., Reibe, S., Estevez, E., Weir, J. et al., Evidence that TLR4 is not a receptor for saturated fatty acids but mediates lipid‐induced inflammation by reprogramming macrophage metabolism. Cell Metab. 2018. 27: 1096–1110. e5.
dc.identifier.citedreferenceKoh, T. J. and DiPietro, L. A. Inflammation and wound healing: the role of the macrophage. Expert Rev. Mol. Med. 2011. 13: e23.
dc.identifier.citedreferenceNa, J., Lee, K., Na, W., Shin, J. ‐. Y., Lee, M. ‐. J., Yune, T. Y., Lee, H. K. et al., Histone H3K27 demethylase JMJD3 in cooperation with NF‐κB regulates keratinocyte wound healing. J. Invest. Dermatol. 2016. 136: 847 – 858.
dc.identifier.citedreferenceNa, J., Shin, J. Y., Jeong, H., Lee, J. Y., Kim, B. J., Kim, W. S., Yune, T. Y. et al., JMJD3 and NF‐κB‐dependent activation of Notch1 gene is required for keratinocyte migration during skin wound healing. Sci. Rep. 2017. 7: 6494.
dc.identifier.citedreferenceClore, J. N., Allred, J., White, D. and Li, J., Stillman, J. The role of plasma fatty acid composition in endogenous glucose production in patients with type 2 diabetes mellitus. Metabolism. 2002. 51: 1471 – 1477.
dc.identifier.citedreferenceTrombetta, A., Togliatto, G., Rosso, A., Dentelli, P., Olgasi, C., Cotogni, P. and Brizzi, M. F. Increase of palmitic acid concentration impairs endothelial progenitor cell and bone marrow‐derived progenitor cell bioavailability: role of the STAT5/PPARγ transcriptional complex. Diabetes. 2013. 62: 1245 – 1257.
dc.identifier.citedreferenceYu, S., Chen, X., Xiu, M., He, F., Xing, J., Min, D. and Guo, F. The regulation of Jmjd3 upon the expression of NF‐κB downstream inflammatory genes in LPS activated vascular endothelial cells. Biochem. Biophys. Res. Commun. 2017. 485: 62 – 68.
dc.identifier.citedreferenceWelstead, G. G., Creyghton, M. P., Bilodeau, S., Cheng, A. W., Markoulaki, S., Young, R. A. and Jaenisch, R. X‐linked H3K27me3 demethylase Utx is required for embryonic development in a sex‐specific manner. Proc. Natl. Acad. Sci. U. S. A. 2012. 109: 13004 – 13009.
dc.identifier.citedreferenceChawla, A., Nguyen, K. D. and Goh, Y. P. S. Macrophage‐mediated inflammation in metabolic disease. Nat. Rev. Immunol. 2011. 11: 738 – 749.
dc.owningcollnameInterdisciplinary and Peer-Reviewed


Files in this item

Name:
eji4870.pdf
Size:
2.097MB
Format:
PDF
View/Open
Name:
eji4870-sup-0001-SuppMat.pdf
Size:
8.195MB
Format:
PDF
View/Open
Name:
eji4870_am.pdf
Size:
1.286MB
Format:
PDF
View/Open

Show simple item record

Remediation of Harmful Language

The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.

Accessibility

If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.