Effect of IL-34 on Macrophage Polarization

Abstract

A cytokine recently found to play a role in monocyte survival has been termed interleukin 34 (IL-34). This cytokine plays a significant role in various physiological processes, including the regulation of cytokine and chemokine expression, differentiation of immune cells, and cell proliferation. In pathological conditions, IL-34 may mirror the pathophysiology of the disease involved, and simultaneously promote the growth and survival of myeloid cells, thereby maintaining homeostasis in the body. Increased levels of IL-34 have been shown in inflammation, autoimmune diseases, infections, and cancer. However, some studies reported that decreased levels IL-34 can be associated with several conditions such as neurological diseases.IL-34 macrophage phenotype is controlled with an immunosuppressive activity. Macrophages are heterogeneous both in function and phenotype. Depending on its biological characteristics and activity on macrophage polarization, IL-34 has been believed to have a therapeutic potential in the treatment of some diseases. The aim of this review is to discuss the role of IL-34 on macrophage polarization.

Keywords

• CSF-1R
• IL-34
• immunotherapy
• macrophage
• macrophage polarization

Supporting Institution

This study did not receive any financial support.

Ethical Statement

There is no need to obtain ethics committee permission for this review article. However, the study was conducted in accordance with ethical principles.

References

1. Amos, P. J., Fung, S., Case, A., Kifelew, J., Osnis, L., Smith, C. L., Green, K., Naydenov, A., Aloi, M., Hubbard, J. J., Ramakrishnan, A., Garden, G. A., & Jayadev, S. (2017). Modulation of Hematopoietic Lineage Specification Impacts TREM2 Expression in Microglia-Like Cells Derived From Human Stem Cells. American Society for Neurochemistry, 9(4), 1759091417716610. https://doi.org/10.1177/1759091417716610
2. Arango Duque, G., & Descoteaux, A. (2014). Macrophage cytokines: involvement in immunity and infectious diseases. Frontiers in Immunology, 5, 491. https://doi.org/10.3389/fimmu.2014.00491
3. Baghdadi, M., Endo, H., Tanaka, Y., Wada, H., & Seino, K.-i. (2017). Interleukin 34, from pathogenesis to clinical applications. Cytokine, 99, 139-147. https://doi.org/10.1016/j.cyto.2017.08.020
4. Baghdadi, M., Umeyama, Y., Hama, N., Kobayashi, T., Han, N., Wada, H., & Seino, K.-i. (2018). Interleukin-34, a comprehensive review. Journal of Leukocyte Biology, 104(5), 931-951. https://doi.org/10.1002/JLB.MR1117-457R
5. Bézie, S., Picarda, E., Ossart, J., Tesson, L., Usal, C., Renaudin, K., Anegon, I., & Guillonneau, C. (2015). IL-34 is a Treg-specific cytokine and mediates transplant tolerance. The Journal of Clinical Investigation, 125(10), 3952-3964. https://doi.org/10.1172/JCI81227.
6. Booker, B. E., Clark, R. S., Pellom, S. T., & Adunyah, S. E. (2015). Interleukin-34 induces monocytic-like differentiation in leukemia cell lines. International Journal of Biochemistry and Molecular Biology, 6(1), 1-16. https://www.ncbi.nlm.nih.gov/pubmed/26045972
7. Boström, E. A., & Lundberg, P. (2013). The newly discovered cytokine IL-34 is expressed in gingival fibroblasts, shows enhanced expression by pro-inflammatory cytokines, and stimulates osteoclast differentiation. PloS One, 8(12), e81665. https://doi.org/10.1371/journal.pone.0081665
8. Boulakirba, S., Pfeifer, A., Mhaidly, R., Obba, S., Goulard, M., Schmitt, T., Chaintreuil, P., Calleja, A., Furstoss, N., & Orange, F. (2018). IL-34 and CSF-1 display an equivalent macrophage differentiation ability but a different polarization potential. Scientific Reports. 8, 256. In. https://doi.org/10.1038/s41598-017-18433-4.

9. Catalan-Dibene, J., McIntyre, L. L., & Zlotnik, A. (2018). Interleukin 30 to interleukin 40. Journal of Interferon & Cytokine Research, 38(10), 423-439. https://doi.org/10.1089/jir.2018.0089.
10. Chang, E.-J., Lee, S. K., Song, Y. S., Jang, Y. J., Park, H. S., Hong, J. P., Ko, A. R., Kim, D. Y., Kim, J.-H., & Lee, Y. J. (2014). IL-34 is associated with obesity, chronic inflammation, and insulin resistance. The Journal of Clinical Endocrinology & Metabolism, 99(7), E1263-E1271. https://doi.org/10.1210/jc.2013-4409
11. Chemel, M., Brion, R., Segaliny, A.-I., Lamora, A., Charrier, C., Brulin, B., Maugars, Y., Le Goff, B., Heymann, D., & Verrecchia, F. (2017). Bone morphogenetic protein 2 and transforming growth factor β1 inhibit the expression of the proinflammatory cytokine IL-34 in rheumatoid arthritis synovial fibroblasts. The American Journal of Pathology, 187(1), 156-162. https://doi.org/10.1016/j.ajpath.2016.09.015
12. Chen, Z., Buki, K., Vaaraniemi, J., Gu, G., & Vaananen, H. K. (2011). The critical role of IL-34 in osteoclastogenesis. PLoS One, 6(4), e18689. https://doi.org/10.1371/journal.pone.0018689
13. Cheng, S. T., Tang, H., Ren, J. H., Chen, X., Huang, A. L., & Chen, J. (2017). Interleukin-34 inhibits hepatitis B virus replication in vitro and in vivo. PLoS One, 12(6), e0179605. https://doi.org/10.1371/journal.pone.0179605
14. Chihara, T., Suzu, S., Hassan, R., Chutiwitoonchai, N., Hiyoshi, M., Motoyoshi, K., Kimura, F., & Okada, S. (2010). IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death & Differentiation, 17(12), 1917-1927. https://doi.org/10.1038/cdd.2010.60
15. Covaleda, L., Fuller, F. J., & Payne, S. L. (2010). EIAV S2 enhances pro-inflammatory cytokine and chemokine response in infected macrophages. Virology, 397(1), 217-223. https://doi.org/10.1016/j.virol.2009.11.005
16. Davies, L. C., Jenkins, S. J., Allen, J. E., & Taylor, P. R. (2013). Tissue-resident macrophages. Nature Immunology, 14(10), 986-995. https://doi.org/10.1038/ni.2705
17. Eda, H., Shimada, H., Beidler, D. R., & Monahan, J. B. (2011). Proinflammatory cytokines, IL-1beta and TNF-alpha, induce expression of interleukin-34 mRNA via JNK- and p44/42 MAPK-NF-kappaB pathway but not p38 pathway in osteoblasts. Rheumatology International, 31(11), 1525-1530. https://doi.org/10.1007/s00296-010-1688-7
18. Endo, H., Hama, N., Baghdadi, M., Ishikawa, K., Otsuka, R., Wada, H., Asano, H., Endo, D., Konno, Y., Kato, T., Watari, H., Tozawa, A., Suzuki, N., Yokose, T., Takano, A., Kato, H., Miyagi, Y., Daigo, Y., & Seino, K. I. (2020). Interleukin-34 expression in ovarian cancer: a possible correlation with disease progression. International Immunology, 32(3), 175-186. https://doi.org/10.1093/intimm/dxz074
19. Fan, Q., Yan, X., Zhang, H., Lu, L., Zhang, Q., & Wang, F. IL-34 is associated with the presence and severity of renal dysfunction and coronary artery disease in patients with heart failure. Scientific Reports. 2016; 6: 39324. In. doi: 10.1038/srep39324
20. Foucher, E. D., Blanchard, S., Preisser, L., Garo, E., Ifrah, N., Guardiola, P., Delneste, Y., & Jeannin, P. (2013). IL-34 induces the differentiation of human monocytes into immunosuppressive macrophages. antagonistic effects of GM-CSF and IFNγ. PloS one, 8(2), e56045. https://doi.org/10.1371/journal.pone.0056045
21. Franze, E., Marafini, I., De Simone, V., Monteleone, I., Caprioli, F., Colantoni, A., Ortenzi, A., Crescenzi, F., Izzo, R., Sica, G., Sileri, P., Rossi, P., Pallone, F., & Monteleone, G. (2016). Interleukin-34 Induces Cc-chemokine Ligand 20 in Gut Epithelial Cells. Journal of Crohn's and Colitis, 10(1), 87-94. https://doi.org/10.1093/ecco-jcc/jjv181
22. Franze, E., Marafini, I., Troncone, E., Salvatori, S., & Monteleone, G. (2021). Interleukin-34 promotes tumorigenic signals for colon cancer cells. Cell Death Discovery, 7(1), 245. https://doi.org/10.1038/s41420-021-00636-4
23. Franze, E., Monteleone, I., Cupi, M. L., Mancia, P., Caprioli, F., Marafini, I., Colantoni, A., Ortenzi, A., Laudisi, F., Sica, G., Sileri, P., Pallone, F., & Monteleone, G. (2015). Interleukin-34 sustains inflammatory pathways in the gut. Clinical Science (London), 129(3), 271-280. https://doi.org/10.1042/CS20150132
24. Franzè, E., Stolfi, C., Troncone, E., Scarozza, P., & Monteleone, G. (2020). Role of interleukin-34 in cancer. Cancers, 12(1), 252. https://doi.org/10.3390/cancers12010252
25. Freuchet, A., Salama, A., Bezie, S., Tesson, L., Remy, S., Humeau, R., Regue, H., Serazin, C., Flippe, L., Peterson, P., Vimond, N., Usal, C., Menoret, S., Heslan, J. M., Duteille, F., Blanchard, F., Giral, M., Colonna, M., Anegon, I., & Guillonneau, C. (2022). IL-34 deficiency impairs FOXP3(+) Treg function in a model of autoimmune colitis and decreases immune tolerance homeostasis. Clinical and Translational Medicine, 12(8), e988. https://doi.org/10.1002/ctm2.988
26. Freuchet, A., Salama, A., Remy, S., Guillonneau, C., & Anegon, I. (2021). IL-34 and CSF-1, deciphering similarities and differences at steady state and in diseases. Journal of leukocyte biology, 110(4), 771-796. https://doi.org/10.1002/JLB.3RU1120-773R
27. Galván-Peña, S., & O’Neill, L. (2014). Metabolic reprograming in macrophage polarization. Frontiers in immunology 5: 420. In. https://doi.org/10.3389/fimmu.2014.00420
28. Ge, Y., Huang, M., & Yao, Y.-m. (2019). Immunomodulation of interleukin-34 and its potential significance as a disease biomarker and therapeutic target. International Journal of Biological Sciences, 15(9), 1835. doi: 10.7150/ijbs.35070
29. Gordon, S. (2016). Phagocytosis: An Immunobiologic Process. Immunity, 44(3), 463-475. https://doi.org/10.1016/j.immuni.2016.02.026
30. Gordon, S., & Martinez, F. O. (2010). Alternative activation of macrophages: mechanism and functions. Immunity, 32(5), 593-604. doi 10.1016/j.immuni.2010.05.007
31. Gordon, S., & Pluddemann, A. (2017). Tissue macrophages: heterogeneity and functions. Biomed Central Biology, 15(1), 53. https://doi.org/10.1186/s12915-017-0392-4
32. Guilliams, M., Thierry, G. R., Bonnardel, J., & Bajenoff, M. (2020). Establishment and Maintenance of the Macrophage Niche. Immunity, 52(3), 434-451. https://doi.org/10.1016/j.immuni.2020.02.015
33. Guillonneau, C., Bézie, S., & Anegon, I. (2017). Immunoregulatory properties of the cytokine IL-34. Cellular and Molecular Life Sciences, 74(14), 2569-2586. doi 10.1007/s00018-017-2482-4
34. Han, C. Z., & Ravichandran, K. S. (2011). Metabolic connections during apoptotic cell engulfment. Cell, 147(7), 1442-1445. https://doi.org/10.1016/j.cell.2011.12.006
35. Hashimoto, D., Chow, A., Noizat, C., Teo, P., Beasley, M. B., Leboeuf, M., Becker, C. D., See, P., Price, J., & Lucas, D. (2013). Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity, 38(4), 792-804. http://dx.doi.org/10.1016/j.immuni.2013.04.004
36. Hu, X., Huang, F., Deng, Y., Wang, J., & Wang, J. (2020). The multifactorial roles of IL-34 in immune responses. Annals of Blood, 5. doi: 10.21037/aob.2019.12.05
37. Kawabe, M., Ohyama, H., Kato-Kogoe, N., Yamada, N., Yamanegi, K., Nishiura, H., Hirano, H., Kishimoto, H., & Nakasho, K. (2015). Expression of interleukin-34 and colony stimulating factor-1 in the stimulated periodontal ligament cells with tumor necrosis factor-alpha. Medical Molecular Morphology, 48(3), 169-176. https://doi.org/10.1007/s00795-014-0094-8
38. Kim, J. I., & Turka, L. A. (2015). Transplant tolerance: a new role for IL-34. The Journal of Clinical Investigation, 125(10), 3751-3753. doi:10.1172/JCI84010.
39. Koronyo-Hamaoui, M., Gaire, B. P., Frautschy, S. A., & Alvarez, J. I. (2022). Role of inflammation in neurodegenerative diseases. In (Vol. 13, pp. 958487): Frontiers in Immunology, doi: 10.3389/fimmu.2022.958487
40. Lelios, I., Cansever, D., Utz, S. G., Mildenberger, W., Stifter, S. A., & Greter, M. (2020). Emerging roles of IL-34 in health and disease. Journal of Experimental Medicine, 217(3), e20190290. https://doi.org/10.1084/jem.20190290
41. Li, C., Xu, X., Wei, S., Jiang, P., Xue, L., Wang, J., & Senior, C. (2021). Tumor-associated macrophages: potential therapeutic strategies and future prospects in cancer. Journal for Immunotherapy of Cancer, 9(1), e001341. https://doi.org/10.1136/jitc-2020-001341
42. Lin, H., Lee, E., Hestir, K., Leo, C., Huang, M., Bosch, E., Halenbeck, R., Wu, G., Zhou, A., & Behrens, D. (2008). Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science, 320(5877), 807-811. doi: 10.1126/science.1154370.
43. Liu, C., Chu, D., Kalantar‐Zadeh, K., George, J., Young, H. A., & Liu, G. (2021). Cytokines: from clinical significance to quantification. Advanced Science, 8(15), 2004433. https://doi.org/10.1002/advs.202004433
44. Luo, J., Elwood, F., Britschgi, M., Villeda, S., Zhang, H., Ding, Z., Zhu, L., Alabsi, H., Getachew, R., Narasimhan, R., Wabl, R., Fainberg, N., James, M. L., Wong, G., Relton, J., Gambhir, S. S., Pollard, J. W., & Wyss-Coray, T. (2013). Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival. Journal of Experimental and Clinical Medicine, 210(1), 157-172. https://doi.org/10.1084/jem.20120412
45. Mass, E., Nimmerjahn, F., Kierdorf, K., & Schlitzer, A. (2023). Tissue-specific macrophages: how they develop and choreograph tissue biology. Nature Reviews Immunology, 23(9), 563-579. https://doi.org/10.1038/s41577-023-00848-y
46. McGrath, K. E., Frame, J. M., & Palis, J. (2015). Early hematopoiesis and macrophage development. Seminars in immunology, DOI: 10.1016/j.smim.2016.03.013
47. Monastero, R. N., & Pentyala, S. (2017). Cytokines as biomarkers and their respective clinical cutoff levels. International Journal of Inflammation, 2017(1), 4309485. https://doi.org/10.1155/2017/4309485
48. Monteleone, G., Franzè, E., Maresca, C., Colella, M., Pacifico, T., & Stolfi, C. (2023). Targeted Therapy of Interleukin-34 as a Promising Approach to Overcome Cancer Therapy Resistance. Cancers, 15(3), 971. https://doi.org/ARTN 97110.3390/cancers15030971
49. Muñoz-Garcia, J., Cochonneau, D., Télétchéa, S., Moranton, E., Lanoe, D., Brion, R., Lézot, F., Heymann, M.-F., & Heymann, D. (2021). The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis. Theranostics, 11(4), 1568. doi: 10.7150/thno.50683
50. Nandi, S., Cioce, M., Yeung, Y.-G., Nieves, E., Tesfa, L., Lin, H., Hsu, A. W., Halenbeck, R., Cheng, H.-Y., & Gokhan, S. (2013). Receptor-type protein-tyrosine phosphatase ζ is a functional receptor for interleukin-34. Journal of Biological Chemistry, 288(30), 21972-21986. https://doi.org/10.1074/jbc.M112.442731
51. Nian, Z. G., Dou, Y. C., Shen, Y. Q., Liu, J. T., Du, X. H., Jiang, Y., Zhou, Y. G., Fu, B. Q., Sun, R., Zheng, X. H., Tian, Z. G., & Wei, H. M. (2024). Interleukin-34-orchestrated tumor-associated macrophage reprogramming is required for tumor immune escape driven by p53 inactivation. Immunity, 57(10), 2344-2361. e2347. https://doi.org/10.1016/j.immuni.2024.08.015
52. Rőszer, T. (2015). Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators of inflammation, 2015(1), 816460. https://doi.org/10.1155/2015/816460
53. Schuster, C., Mildner, M., Mairhofer, M., Bauer, W., Fiala, C., Prior, M., Eppel, W., Kolbus, A., Tschachler, E., Stingl, G., & Elbe-Burger, A. (2014). Human embryonic epidermis contains a diverse Langerhans cell precursor pool. Development, 141(4), 807-815. https://doi.org/10.1242/dev.102699
54. Segaliny, A. I., Brion, R., Mortier, E., Maillasson, M., Cherel, M., Jacques, Y., Le Goff, B., & Heymann, D. (2015). Syndecan-1 regulates the biological activities of interleukin-34. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1853(5), 1010-1021. https://doi.org/10.1016/j.bbamcr.2015.01.023
55. Ségaliny, A. I., Mohamadi, A., Dizier, B., Lokajczyk, A., Brion, R., Lanel, R., Amiaud, J., Charrier, C., Boisson‐Vidal, C., & Heymann, D. (2015). Interleukin‐34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment. International journal of cancer, 137(1), 73-85. https://doi.org/10.1002/ijc.29376
56. Shoji, H., Yoshio, S., Mano, Y., Kumagai, E., Sugiyama, M., Korenaga, M., Arai, T., Itokawa, N., Atsukawa, M., & Aikata, H. (2016). Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease. Scientific reports, 6(1), 28814. DOI: 10.1038/srep28814
57. Sprague, A. H., & Khalil, R. A. (2009). Inflammatory cytokines in vascular dysfunction and vascular disease. Biochemical pharmacology, 78(6), 539-552. https://doi.org/10.1016/j.bcp.2009.04.029
58. Stanley, E. R., & Chitu, V. (2014). CSF-1 receptor signaling in myeloid cells. Cold Spring Harbor perspectives in biology, 6(6), a021857. doi: 10.1101/cshperspect.a021857
59. Uhlen, M., Fagerberg, L., Hallstrom, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, A., Kampf, C., Sjostedt, E., Asplund, A., Olsson, I., Edlund, K., Lundberg, E., Navani, S., Szigyarto, C. A., Odeberg, J., Djureinovic, D., Takanen, J. O., Hober, S., . . . Ponten, F. (2015). Proteomics. Tissue-based map of the human proteome. Science, 347(6220), 1260419. https://doi.org/10.1126/science.1260419
60. Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T., & Castegna, A. (2019). The metabolic signature of macrophage responses. Frontiers in Immunology, 10, 1462. https://doi.org/10.3389/fimmu.2019.01462
61. Walker, D. G., Tang, T. M., & Lue, L.-F. (2017). Studies on colony stimulating factor receptor-1 and ligands colony stimulating factor-1 and interleukin-34 in Alzheimer's disease brains and human microglia. Frontiers in Aging Neuroscience, 9, 244. https://doi.org/10.3389/fnagi.2017.00244
62. Wang, H., Cao, J., & Lai, X. (2016). Serum interleukin-34 levels are elevated in patients with systemic lupus erythematosus. Molecules, 22(1), 35. https://doi.org/10.3390/molecules22010035
63. Wang, L. X., Zhang, S. X., Wu, H. J., Rong, X. L., & Guo, J. (2019). M2b macrophage polarization and its roles in diseases. Journal of Leukocyte Biology, 106(2), 345-358. https://doi.org/10.1002/JLB.3RU1018-378RR Wang, N., Liang, H. W., & Zen, K. (2014). Molecular mechanisms that influence the macrophage M1-M2 polarization balance. Frontiers in Immunology, 5, 614. https://doi.org/ARTN 61410.3389/fimmu.2014.00614
64. Wang, Y., Szretter, K. J., Vermi, W., Gilfillan, S., Rossini, C., Cella, M., Barrow, A. D., Diamond, M. S., & Colonna, M. (2012). IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nature immunology, 13(8), 753-760. doi: 10.1038/ni.2360
65. Wang, Z., Ye, C., Zhai, W., Gao, Z., Wang, H., & Liu, H. (2025). Recombinant IL-34 alleviates bacterial enteritis in Megalobrama amblycephala by strengthening the intestinal barrier. International Journal of Biological Macromolecules, 284, 138072. https://doi.org/10.1016/j.ijbiomac.2024.138072
66. Yadav, S., Priya, A., Borade, D. R., & Agrawal-Rajput, R. (2023). Macrophage subsets and their role: co-relation with colony-stimulating factor-1 receptor and clinical relevance. Immunologic Research, 71(2), 130-152. https://doi.org/10.1007/s12026-022-09330-8
67. Yu, Y. Q., Yang, D., Qiu, L. H., Okamura, H., Guo, J. J., & Haneji, T. (2014). Tumor necrosis factor-α induces interleukin-34 expression through nuclear factor-κB activation in MC3T3-E1 osteoblastic cells. Molecular Medicine Reports, 10(3), 1371-1376. https://doi.org/10.3892/mmr.2014.2353
68. Zhang, F., Ding, R., Li, P., Ma, C., Song, D., Wang, X., Ma, T., & Bi, L. (2015). Interleukin-34 in rheumatoid arthritis: potential role in clinical therapy. International journal of clinical and experimental medicine, 8(5), 7809-7815. https://www.ncbi.nlm.nih.gov/pubmed/26221333
69. Zhao, Z., Pan, G., Tang, C., Li, Z., Zheng, D., Wei, X., & Wu, Z. (2018). IL-34 Inhibits Acute Rejection of Rat Liver Transplantation by Inducing Kupffer Cell M2 Polarization. Transplantation, 102(6), e265-e274. https://doi.org/10.1097/TP.0000000000002194.