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Regulatory macrophages

March 03, 2024

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]

Mreg origin and induction edit

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 edit

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 edit

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 edit

  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. ^ a b 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. ^ a b c d e f 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. ^ a b c d e f 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. ^ a b 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. ^ a b 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. ^ a b 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. ^ a b 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. ^ a b 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. ^ a b 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.

March 03, 2024
regulatory, macrophages, mregs, represent, subset, anti, inflammatory, macrophages, general, macrophages, very, dynamic, plastic, cell, type, divided, into, main, groups, classically, activated, macrophages, alternatively, activated, macrophages, group, furthe. 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 b 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 b M2c are induced by glucocorticoids and TGF b 8 M2d are pro angiogenic cells that secrete IL 10 TGF b 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 ReferencesMreg origin and induction editMregs can arise following innate or adaptive immune responses Mregs were first described after FcgR 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 Fcg 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 IFNg 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 editSurprisingly 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 editThe 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 naive helper T cells to Th1 cells which produce high levels of IFNg 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 TGFb PGE2 iNOS IDO and down regulation of IL 1b IL 6 IL 12 and TNF a 21 By secreting TGF b 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 g 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 edit 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 a b 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 Giacomelli R Ruscitti P Alvaro S Ciccia F Liakouli V Di Benedetto P et al August 2016 IL 1b 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 a b c d e f 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 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 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 a b c d e f 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 a b 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 a b 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 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 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 a b 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 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 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 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 a b Koelink PJ Bloemendaal FM Li B Westera L Vogels EW van Roest M et al June 2020 Anti TNF therapy in IBD exerts its therapeutic effect through macrophage IL 10 signalling Gut 69 6 1053 1063 doi 10 1136 gutjnl 2019 318264 PMC 7282553 PMID 31506328 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 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 a b 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 a b 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 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 b Immunology and Cell Biology 94 8 747 62 doi 10 1038 icb 2016 34 PMID 27075967 S2CID 205152075 a b 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 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 Retrieved from https en wikipedia org w index php title Regulatory macrophages amp oldid 1183930456, wikipedia, wiki, book, books, library,

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