Regulatory macrophages

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] 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]

## Contents

* 1 Mreg origin and induction
* 2 Characterization and determination of Mregs
* 3 Biochemical and functional characterization of Mregs
* 4 References

## 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. ↑ "Metabolic regulation of macrophage phenotype and function". Immunological Reviews 280 (1): 102–111. November 2017. doi:10.1111/imr.12603. PMID 29027220.
2. ↑ 2.0 2.1 "Alternative activation of macrophages: mechanism and functions". Immunity 32 (5): 593–604. May 2010. doi:10.1016/j.immuni.2010.05.007. PMID 20510870.
3. ↑ "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. August 2016. doi:10.1586/1744666X.2016.1168293. PMID 26999417.
4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Macrophages with regulatory functions, a possible new therapeutic perspective in autoimmune diseases". Autoimmunity Reviews 18 (10): 102369. October 2019. doi:10.1016/j.autrev.2019.102369. PMID 31404701.
5. ↑ "Complement, c1q, and c1q-related molecules regulate macrophage polarization". Frontiers in Immunology 5: 402. 2014-08-21. doi:10.3389/fimmu.2014.00402. PMID 25191325.
6. ↑ "M2b macrophage polarization and its roles in diseases". Journal of Leukocyte Biology 106 (2): 345–358. August 2019. doi:10.1002/JLB.3RU1018-378RR. PMID 30576000.
7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "The characteristics of regulatory macrophages and their roles in transplantation". International Immunopharmacology 91: 107322. February 2021. doi:10.1016/j.intimp.2020.107322. PMID 33418238.
8. ↑ 8.0 8.1 "Macrophage plasticity, polarization, and function in health and disease". Journal of Cellular Physiology 233 (9): 6425–6440. September 2018. doi:10.1002/jcp.26429. PMID 29319160.
9. ↑ 9.0 9.1 "Role of Human Macrophage Polarization in Inflammation during Infectious Diseases". International Journal of Molecular Sciences 19 (6): 1801. June 2018. doi:10.3390/ijms19061801. PMID 29921749.
10. ↑ "Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors". Journal of Immunology 166 (11): 6861–8. June 2001. doi:10.4049/jimmunol.166.11.6861. PMID 11359846.
11. ↑ "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. December 2007. doi:10.1073/pnas.0706832104. PMID 18042719. Bibcode: 2007PNAS..10419446T.
12. ↑ 12.0 12.1 "Macrophage polarization to a unique phenotype driven by B cells". European Journal of Immunology 40 (8): 2296–307. August 2010. doi:10.1002/eji.200940288. PMID 20468007.
13. ↑ "Glucocorticoids and the Th1/Th2 balance". Annals of the New York Academy of Sciences 1024 (1): 138–46. June 2004. doi:10.1196/annals.1321.010. PMID 15265778. Bibcode: 2004NYASA1024..138E. https://zenodo.org/record/1235876.
14. ↑ "Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization". Blood Advances 2 (21): 2904–2916. November 2018. doi:10.1182/bloodadvances.2018024497. PMID 30396910.
15. ↑ "Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro". Inflammatory Bowel Diseases 18 (3): 401–8. March 2012. doi:10.1002/ibd.21818. PMID 21936028.
16. ↑ 16.0 16.1 "Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling". Gut 69 (6): 1053–1063. June 2020. doi:10.1136/gutjnl-2019-318264. PMID 31506328.
17. ↑ "Regulatory Macrophages Inhibit Alternative Macrophage Activation and Attenuate Pathology Associated with Fibrosis". Journal of Immunology 203 (8): 2130–2140. October 2019. doi:10.4049/jimmunol.1900270. PMID 31541024.
18. ↑ "The generation of macrophages with anti-inflammatory activity in the absence of STAT6 signaling". Journal of Leukocyte Biology 98 (3): 395–407. September 2015. doi:10.1189/jlb.2A1114-560R. PMID 26048978.
19. ↑ 19.0 19.1 "Biochemical and functional characterization of three activated macrophage populations". Journal of Leukocyte Biology 80 (6): 1298–307. December 2006. doi:10.1189/jlb.0406249. PMID 16905575.
20. ↑ 20.0 20.1 "DHRS9 Is a Stable Marker of Human Regulatory Macrophages". Transplantation 101 (11): 2731–2738. November 2017. doi:10.1097/TP.0000000000001814. PMID 28594751.
21. ↑ "Human macrophages induce CD4(+)Foxp3(+) regulatory T cells via binding and re-release of TGF-β". Immunology and Cell Biology 94 (8): 747–62. September 2016. doi:10.1038/icb.2016.34. PMID 27075967.
22. ↑ 22.0 22.1 "TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity". Nature Communications 9 (1): 2858. July 2018. doi:10.1038/s41467-018-05167-8. PMID 30030423. Bibcode: 2018NatCo...9.2858R.
23. ↑ "Persistent lung inflammation and fibrosis in serum amyloid P component (APCs-/-) knockout mice". PLOS ONE 9 (4): e93730. 2014-04-02. doi:10.1371/journal.pone.0093730. PMID 24695531. Bibcode: 2014PLoSO...993730P.

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