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Cyclic GMP-dependent protein kinase II is necessary for macrophage M1 polarization and phagocytosis via toll-like receptor 2

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Abstract

Cyclic GMP-dependent protein kinase II (cGKII; PRKG2) phosphorylates a variety of biological targets and has been identified as a gout-susceptible gene. However, the regulatory role of cGKII in triggering gout disease has yet to be clarified. Thus, we plan to explore the specific function of cGKII in macrophages related to gout disease. By using cGKII gene knockdown method, we detected macrophage M1/M2 polarization, phagocytosis, and their responses to stimulation by monosodium urate (MSU). cGKII was highly expressed in M1 phenotype, but not in M2, and cGKII knockdown significantly inhibited macrophage M1 polarization by decreasing M1 chemokine markers (CXCL10 and CCL2) and downregulating phagocytosis function. We further identified that cGKII-associated phagocytosis was mediated by upregulating toll-like receptor 2 (TLR2) expression, but not by TLR4. Mimicking gout condition by MSU treatments, we found that MSU alone induced cGKII and TLR2 expression with increased M1 polarization markers and phagocytosis activity. It means that cGKII knockdown significantly inhibited this MSU-induced cGKII-TLR2-phagocytosis axis. Our study showed that cGKII plays a key role in M1 polarization, especially in TLR2-mediated phagocytosis under MSU exposure. The findings provide evidence for the possible role of cGKII as an inflammation exciter in gout disease.

Key message

  • Gout-susceptible gene cGKII is necessary for macrophage M1 polarization.

  • cGKII regulates M1 phagocytosis function via TLR2.

  • Monosodium urate treatments increase cGKII expression and related function.

  • This study reveals the role of cGKII in enhancing gouty inflammatory responses.

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Acknowledgments

This work was supported by the grants from the National Science Council (NSC103-2314-B-182A-072, NSC103-2314-B-390-001), and the Kaohsiung Medical University (KMU-M103004, KMU-TP103A24) in Taiwan, and the National Science Foundation in China (NSF 31371272).

Conflict of interest

None.

Author contributions

All authors were involved in writing the article or revising it critically for important intellectual content and approved the final version to be published. Dr. Liao WT, Chang SJ, and Chen CJ had full access to all of the data in the study and take responsibility for the accuracy of the data. Wei-Ting Liao contributed to the study design and experimental processing and wrote the Methods, Results, and Discussion. Huey-Ling You designed and performed the experiments. Changgui Li contributed to the technical support in cGKII pathway. Jan-Gowth Chang contributed to the organization of the study design and data analysis. Shun-Jen Chang wrote the Discussion, contributed to the study idea, and directed the study focus. Chung-Jen Chen contributed to the study design and result interpretation and wrote the Introduction and Discussion.

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Authors and Affiliations

  1. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan

    Wei-Ting Liao

  2. Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan

    Wei-Ting Liao

  3. Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Huey-Ling You

  4. Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China

    Changgui Li

  5. Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan

    Jan-Gowth Chang

  6. School of Medicine, China Medical University, Taichung, Taiwan

    Jan-Gowth Chang

  7. Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, No. 700, Kaohsiung University Rd, Nanzih District, 811, Kaohsiung, Taiwan

    Shun-Jen Chang

  8. Division of General Internal Medicine, Kaohsiung Medical University Hospital, No. 100 Tzyou 1st Road, Kaohsiung, Taiwan

    Chung-Jen Chen

Authors
  1. Wei-Ting Liao
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  2. Huey-Ling You
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  3. Changgui Li
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  4. Jan-Gowth Chang
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Correspondence to Shun-Jen Chang or Chung-Jen Chen.

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Liao, WT., You, HL., Li, C. et al. Cyclic GMP-dependent protein kinase II is necessary for macrophage M1 polarization and phagocytosis via toll-like receptor 2. J Mol Med 93, 523–533 (2015). https://doi.org/10.1007/s00109-014-1236-0

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  • DOI: https://doi.org/10.1007/s00109-014-1236-0

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