Regulatory macrophages

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Regulatory macrophages (Mregs) represent a subset of anti-inflammatory macrophages. In general, macrophages are a very dynamic and plastic cell type and can be divided into two main groups: classically activated macrophages (M1) and alternatively activated macrophages (M2). [1] M2 group can further be divided into sub-groups M2a, M2b, M2c, and M2d. [2] Typically the M2 cells have anti-inflammatory and regulatory properties and produce many different anti-inflammatory cytokines such as IL-4, IL-33, IL-10, IL-1RA, and TGF-β. [3] [4] M2 cells can also secrete angiogenic and chemotactic factors. [5] These cells can be distinguished based on the different expression levels of various surface proteins and the secretion of different effector molecules. [4]

Contents

M2a, mainly known as alternatively activated macrophages, are macrophages associated with tissue healing due to the production of components of extracellular matrix. M2a cells are induced by IL-4 and IL-13. [2] M2b, generally referred to as regulatory macrophages (Mregs), are characterized by secreting large amounts of IL-10 and small amounts of IL-12. [6] [7] M2c, also known as deactivated macrophages, secrete large amounts of IL-10 and TGF-β. M2c are induced by glucocorticoids and TGF-β. [8] M2d are pro-angiogenic cells that secrete IL-10, TGF-β, and vascular endothelial growth factor and are induced by IL-6 and A2 adenosine receptor agonist (A2R). [4] [9]

Mreg origin and induction

Mregs can arise following innate or adaptive immune responses. Mregs were first described after FcγR ligation by IgG complexes in the occurrence of pathogen-associated molecular patterns (e. g. lipopolysaccharide or lipoteichoic acid) acting through Toll-like receptors. [10] Coculture of macrophages with regulatory T cells (Tregs) caused differentiation of macrophages toward Mreg phenotype. [11] Similar effect provoked interaction of macrophages and B1 B cells. [12] Mregs can even arise following stress responses. Activation of the hypothalamic-pituitary-adrenal axis leads to production of glucocorticoids that cause decreased production of IL-12 by macrophages. [13]

Many cell types including monocytes, M1, and M2 can in a specific microenvironment differentiate to Mregs. [7] Induction of Mregs is strongly linked with the interaction of Fc receptors located on the surface of Mregs with Fc fragments of antibodies. [14] It has been shown that anti-TNF monoclonal antibodies interacting with Fcγ receptor of Mregs induce differentiation of Mregs through activation of STAT3 signaling pathway. [15] [16] Some pathogens can promote the transformation of cells into Mregs as an immune evasion mechanism. [7] [17] Two signals are needed for Mregs inducement. The first signal is stimulation by M-CSF, GM-CSF, PGE2, adenosine, glucocorticoid, or apoptotic cells. [9] [18] The second signal can be stimulation with cytokines or toll-like receptor ligands. The first signal promotes the differentiation of monocytes to macrophages and the second signal promotes immunosuppressive functions. [8] In vitro, M-CSF, IFNγ, and LPS are used for the inducement of Mregs. [7]

Other cells such as eosinophils and innate lymphoid cells type 2 (ILC2) can promote M2 polarization by cytokine secretion. IL-9 can function as a growth factor for ILC-2 and thereby assist in the induction of Mregs. Another cytokine that helps the induction of Mregs is IL-35 which is produced by Tregs. [7]

Characterization and determination of Mregs

Surprisingly, Mregs resemble classically activated macrophages more than alternatively activated macrophages, due to higher biochemical similarity. [19] The difference between M1 macrophages and Mregs is, inter alia, that Mregs secrete high levels of IL-10 and simultaneously low levels of IL-12. Out of all macrophages, Mregs show the highest expression of MHC II molecules and co-stimulatory molecules (CD80/CD86), which differentiates them from the alternatively activated macrophages, which show a very low expression of these molecules. Mregs also differ from alternatively activated macrophages by producing high levels of nitric oxide and low arginase activity. [7] [16] [19] Lastly, they differ in the expression of FIIZ1 (Resistin-like molecule alpha1) and YM1 which are differentiation markers present on alternatively activated macrophages. [4] Mregs are recognized by the expression of PD-L1, CD206, CD80/CD86, HLA-DR, and DHRS9 (dehydrogenase/reductase 9). [4] [20] DHRS9 has been recognized as a stable marker for Mregs in humans. [20]

Biochemical and functional characterization of Mregs

The physiological role of Mregs is to dampen the immune response and immunopathology. Unlike classically activated macrophages, Mregs produce low levels of IL-12, which is important because IL-12 induces differentiation of naïve helper T cells to Th1 cells which produce high levels of IFNγ. Mregs do not contribute to the production of extracellular matrix because they express low levels of arginase. [12] [4]

Mregs show up-regulation of IL-10, TGFβ, PGE2, iNOS, IDO, and down-regulation of IL-1β, IL-6, IL-12, and TNF-α. [21] By secreting TGF-β they help with the induction of Tregs and by producing IL-10 they contribute to the induction of tolerance and regulatory cell types. Mregs can directly inhibit the proliferation of activated T cells. It has been shown that Mregs co-cultured with T cells have a negative effect on the T-cellular ability to secrete IL-2 and IFN-γ. [22] Mregs can also inhibit the arginase activity of alternatively activated macrophages, the proliferation of fibroblasts, and can promote angiogenesis. [23] The use of Mregs is widely studied as a potential cell-based immunosuppressive therapy after organ transplantation. Mregs could potentially solve the problems (susceptibility to infectious diseases and cancer diseases) associated with the current post-transplant therapy. Since Mregs are still producing nitric oxide they may be more suitable than current treatments, when appropriately stimulated. [22]

References

  1. ↑ Saha S, Shalova IN, Biswas SK (November 2017). "Metabolic regulation of macrophage phenotype and function". Immunological Reviews. 280 (1): 102–111. doi:10.1111/imr.12603. PMID   29027220. S2CID   36334334.
  2. 1 2 Gordon S, Martinez FO (May 2010). "Alternative activation of macrophages: mechanism and functions". Immunity. 32 (5): 593–604. doi: 10.1016/j.immuni.2010.05.007 . PMID   20510870.
  3. ↑ Giacomelli R, Ruscitti P, Alvaro S, Ciccia F, Liakouli V, Di Benedetto P, et al. (August 2016). "IL-1β at the crossroad between rheumatoid arthritis and type 2 diabetes: may we kill two birds with one stone?". Expert Review of Clinical Immunology. 12 (8): 849–55. doi:10.1586/1744666X.2016.1168293. hdl: 10447/207730 . PMID   26999417. S2CID   23523228.
  4. 1 2 3 4 5 6 Di Benedetto P, Ruscitti P, Vadasz Z, Toubi E, Giacomelli R (October 2019). "Macrophages with regulatory functions, a possible new therapeutic perspective in autoimmune diseases". Autoimmunity Reviews. 18 (10): 102369. doi:10.1016/j.autrev.2019.102369. PMID   31404701. S2CID   199548742.
  5. ↑ Bohlson SS, O'Conner SD, Hulsebus HJ, Ho MM, Fraser DA (2014-08-21). "Complement, c1q, and c1q-related molecules regulate macrophage polarization". Frontiers in Immunology. 5: 402. doi: 10.3389/fimmu.2014.00402 . PMC   4139736 . PMID   25191325.
  6. ↑ Wang LX, Zhang SX, Wu HJ, Rong XL, Guo J (August 2019). "M2b macrophage polarization and its roles in diseases". Journal of Leukocyte Biology. 106 (2): 345–358. doi:10.1002/JLB.3RU1018-378RR. PMC   7379745 . PMID   30576000.
  7. 1 2 3 4 5 6 Zhang F, Zhang J, Cao P, Sun Z, Wang W (February 2021). "The characteristics of regulatory macrophages and their roles in transplantation". International Immunopharmacology. 91: 107322. doi:10.1016/j.intimp.2020.107322. PMID   33418238. S2CID   231302026.
  8. 1 2 Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. (September 2018). "Macrophage plasticity, polarization, and function in health and disease". Journal of Cellular Physiology. 233 (9): 6425–6440. doi: 10.1002/jcp.26429 . PMID   29319160. S2CID   3621509.
  9. 1 2 Atri C, Guerfali FZ, Laouini D (June 2018). "Role of Human Macrophage Polarization in Inflammation during Infectious Diseases". International Journal of Molecular Sciences. 19 (6): 1801. doi: 10.3390/ijms19061801 . PMC   6032107 . PMID   29921749.
  10. ↑ Gerber JS, Mosser DM (June 2001). "Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors". Journal of Immunology. 166 (11): 6861–8. doi: 10.4049/jimmunol.166.11.6861 . PMID   11359846.
  11. ↑ Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (December 2007). "CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages". Proceedings of the National Academy of Sciences of the United States of America. 104 (49): 19446–51. Bibcode:2007PNAS..10419446T. doi: 10.1073/pnas.0706832104 . PMC   2148309 . PMID   18042719.
  12. 1 2 Wong SC, Puaux AL, Chittezhath M, Shalova I, Kajiji TS, Wang X, et al. (August 2010). "Macrophage polarization to a unique phenotype driven by B cells". European Journal of Immunology. 40 (8): 2296–307. doi:10.1002/eji.200940288. PMID   20468007.
  13. ↑ Elenkov IJ (June 2004). "Glucocorticoids and the Th1/Th2 balance". Annals of the New York Academy of Sciences. 1024 (1): 138–46. Bibcode:2004NYASA1024..138E. doi:10.1196/annals.1321.010. PMID   15265778. S2CID   9575617.
  14. ↑ Kis-Toth K, Rajani GM, Simpson A, Henry KL, Dumont J, Peters RT, et al. (November 2018). "Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization". Blood Advances. 2 (21): 2904–2916. doi:10.1182/bloodadvances.2018024497. PMC   6234359 . PMID   30396910.
  15. ↑ Vos AC, Wildenberg ME, Arijs I, Duijvestein M, Verhaar AP, de Hertogh G, et al. (March 2012). "Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro". Inflammatory Bowel Diseases. 18 (3): 401–8. doi: 10.1002/ibd.21818 . PMID   21936028. S2CID   43842814.
  16. ↑ Chandrasekaran P, Izadjoo S, Stimely J, Palaniyandi S, Zhu X, Tafuri W, Mosser DM (October 2019). "Regulatory Macrophages Inhibit Alternative Macrophage Activation and Attenuate Pathology Associated with Fibrosis". Journal of Immunology. 203 (8): 2130–2140. doi: 10.4049/jimmunol.1900270 . PMID   31541024. S2CID   202711008.
  17. ↑ Fleming BD, Chandrasekaran P, Dillon LA, Dalby E, Suresh R, Sarkar A, et al. (September 2015). "The generation of macrophages with anti-inflammatory activity in the absence of STAT6 signaling". Journal of Leukocyte Biology. 98 (3): 395–407. doi:10.1189/jlb.2A1114-560R. PMC   4541501 . PMID   26048978.
  18. 1 2 Edwards JP, Zhang X, Frauwirth KA, Mosser DM (December 2006). "Biochemical and functional characterization of three activated macrophage populations". Journal of Leukocyte Biology. 80 (6): 1298–307. doi:10.1189/jlb.0406249. PMC   2642590 . PMID   16905575.
  19. 1 2 Riquelme P, Amodio G, Macedo C, Moreau A, Obermajer N, Brochhausen C, et al. (November 2017). "DHRS9 Is a Stable Marker of Human Regulatory Macrophages". Transplantation. 101 (11): 2731–2738. doi:10.1097/TP.0000000000001814. PMC   6319563 . PMID   28594751.
  20. ↑ Schmidt A, Zhang XM, Joshi RN, Iqbal S, Wahlund C, Gabrielsson S, et al. (September 2016). "Human macrophages induce CD4(+)Foxp3(+) regulatory T cells via binding and re-release of TGF-β". Immunology and Cell Biology. 94 (8): 747–62. doi:10.1038/icb.2016.34. PMID   27075967. S2CID   205152075.
  21. 1 2 Riquelme P, Haarer J, Kammler A, Walter L, Tomiuk S, Ahrens N, et al. (July 2018). "TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity". Nature Communications. 9 (1): 2858. Bibcode:2018NatCo...9.2858R. doi:10.1038/s41467-018-05167-8. PMC   6054648 . PMID   30030423.
  22. ↑ Pilling D, Gomer RH (2014-04-02). Zissel G (ed.). "Persistent lung inflammation and fibrosis in serum amyloid P component (APCs-/-) knockout mice". PLOS ONE. 9 (4): e93730. Bibcode:2014PLoSO...993730P. doi: 10.1371/journal.pone.0093730 . PMC   3973556 . PMID   24695531.
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