TY  - JOUR
T1  - Effect of IL-34 on Macrophage Polarization
AU  - Sarper, Meral
AU  - Karakuş, Resul
PY  - 2025
DA  - September
Y2  - 2025
DO  - 10.59124/guhes.1648625
JF  - Journal of Gazi University Health Sciences Institute
JO  - GUHES
PB  - Gazi University
WT  - DergiPark
SN  - 2687-6353
SP  - 46
EP  - 57
VL  - 7
IS  - 2
LA  - en
AB  - 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.
KW  - CSF-1R
KW  - IL-34
KW  - immunotherapy
KW  - macrophage
KW  - macrophage polarization
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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.
CR  - 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
CR  - 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
CR  - 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.
CR  - 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.
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - Gordon, S. (2016). Phagocytosis: An Immunobiologic Process. Immunity, 44(3), 463-475. https://doi.org/10.1016/j.immuni.2016.02.026
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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.
CR  - 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
CR  - 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
CR  - 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
CR  - 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.
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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
CR  - 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.
UR  - https://doi.org/10.59124/guhes.1648625
L1  - https://dergipark.org.tr/en/download/article-file/4648843
ER  -