Abstract
Chronic inflammation of the gastrointestinal system is mediated by both the immune system activity and homeostasis, mainly through releasing of various cytokines and chemokines, as well as the transmigration of the inflammatory cells to the affected site. In between, macrophages are key mediators of the immune system, nearly located all over the gastrointestinal tract. Macrophages have vital influence on the inflammatory condition with both pro-inflammatory and anti-inflammatory functions. Their polarization status has been linked to numerous metabolic disorders such as inflammatory bowel disease (IBD). The equilibrium between the phenotypes and functions of inflammatory M1 and anti-inflammatory M2 cells is regulated by both extracellular and intracellular stimuli, determining how the disease progresses. Thereby, factors that interchange such balance in the direction of increasing M2 macrophages offer unique approaches for future management of IBD. This study reflects the novel IBD treatment targets via the immune system’s pathway, reporting the latest treatments that regulate the M1/M2 macrophages distribution in a way to favor IBD.
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Abraham BP, Quigley EMM (2017) Probiotics in inflammatory bowel disease. Gastroenterol Clin North Am 46:769–782
Abron JD, Singh NP, Price RL, Nagarkatti M, Nagarkatti PS, Singh UP (2018) Genistein induces macrophage polarization and systemic cytokine to ameliorate experimental colitis. PLoS One 13(7):e0199631. https://doi.org/10.1371/journal.pone.0199631
Almeida JRGdS, Souza GR, Silva JC, Saraiva SRGdL, Júnior RGdO, Quintans JdSS, Junior LJQ (2013) Borneol, a bicyclic monoterpene alcohol, reduces nociceptive behavior and inflammatory response in mice. Sci World J. https://doi.org/10.1155/2013/808460
Bain CC, Mowat AM (2014) Macrophages in intestinal homeostasis and inflammation. Immunol Rev 260(1):102–117
Bosma M, Gerling M, Pasto J, Georgiadi A, Graham E, Shilkova O, Toftgård R (2016) FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice. Nat Commun 7:11314. https://doi.org/10.1038/ncomms11314
Che X, Park KC, Park SJ, Kang YH, Jin HA, Kim JW, Kim WH (2018) Protective effects of guggulsterone against colitis are associated with the suppression of TREM-1 and modulation of macrophages. Am J Physiol Gastrointest Liver Physiol 315(1):G128–G139
Cheng Z, Hl Peng, Zhang R, Fu XM, Gs Zhang (2017) Bone marrow-derived innate macrophages attenuate oxazolone-induced colitis. Cell Immunol 311:46–53
Chiu CY, Gomolka B, Dierkes C, Huang NR, Schroeder M, Purschke M, Weylandt KH (2012) Omega-6 docosapentaenoic acid-derived resolvins and 17-hydroxydocosahexaenoic acid modulate macrophage function and alleviate experimental colitis. Inflamm Res 61(9):967–976
Choi H, Lee RH, Bazhanov N, Oh JY, Prockop DJ (2011) Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages. Blood 118(2):330–338
Connell M, Shin A, James-Stevenson T, Xu H, Imperiale T, Herron J (2018) Systematic review and meta-analysis: efficacy of patented probiotic, VSL# 3, in irritable bowel syndrome. Neurogastroenterol Motil 30(12):e13427. https://doi.org/10.1111/nmo.13427
Cosín-Roger J, Ortiz-Masiá D, Calatayud S, Hernández C, Álvarez A, Hinojosa J et al (2013) M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis. PLoS One 8(10):e78128
Cui H, Cai Y, Wang L, Jia B, Li J, Zhao S, Bian Y (2018) Berberine regulates Treg/Th17 balance to treat ulcerative colitis through modulating the gut microbiota in the colon. Front Pharmacol 9:571. https://doi.org/10.3389/fphar.2018.00571
Dalessio S, Correale C, Tacconi C, Gandelli A, Pietrogrande G, Vetrano S, Peyrin-Biroulet L (2014) VEGF-C-dependent stimulation of lymphatic function ameliorates experimental inflammatory bowel disease. J Clin Invest 124(9):3863–3878
Danchuk S, Ylostalo JH, HossainF Sorge R, Ramsey A, Bonvillain RW, Prockop DJ (2011) Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-α-induced protein 6. Stem Cell Res Ther 2(3):27. https://doi.org/10.1186/scrt68
Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Maisonpierre PC (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87(7):1161–1169
Dia VP, Berhow MA, Gonzalez De Mejia E (2008) Bowman-birk inhibitor and genistein among soy compounds that synergistically inhibit nitric oxide and prostaglandin E2 pathways in lipopolysaccharide-induced macrophages. J Agric Food Chem 56(24):11707–11717
Dionne S, Duchatelier CF, Seidman EG (2017) The influence of vitamin D on M1 and M2 macrophages in patients with Crohn’s disease. J Innate Immun 23(6):557–565
Farzaei MH, Bahramsoltani R, Abdolghaffari AH, Sodagari HR, Esfahani SA, Rezaei N (2016) A mechanistic review on plant-derived natural compounds as dietary supplements for prevention of inflammatory bowel disease. Expert Rev Gastroent 10(6):745–758
Farzaei MH, El-Senduny FF, Momtaz S, Parvizi F, Iranpanah A, Tewari D, Naseri R, Abdolghaffari AH, Rezaei N (2018) An update on dietary consideration in inflammatory bowel disease: anthocyanins and more. Expert Rev Gastroent 12(10):1007–1024
Foey A (2015) Macrophage polarization: A collaboration of differentiation, activation and pre-programming. J Clin Cell Immunol 6:293. https://doi.org/10.4172/2155-9899.1000293
Gionchetti P, Calabrese C, Calafiore A, Rizzello F (2017) Probiotics, prebiotics, and antibiotics in IBD. Crohn’s disease and Ulcerative colitis. Springer, Cham, pp 455–469
Grainger JR, Konkel JE, Zangerle-Murray T, Shaw TN (2017) Macrophages in gastrointestinal homeostasis and inflammation. Pflugers Arch 469(3–4):527–539
Hidalgo-Garcia L, Galvez J, Rodriguez-Cabezas ME, Anderson PO (2018) Can a conversation between mesenchymal stromal cells and macrophages solve the crisis in the inflamed intestine? Front Pharmacol 9:179. https://doi.org/10.3389/fphar.2018.00179
Hunter MM, Wang A, Parhar KS, Johnston MJ, Van Rooijen N, Beck PL, McKay DM (2010) In vitro-derived alternatively activated macrophages reduce colonic inflammation in mice. Gastroenterology 138(4):1395–1405
Hyam SR, Lee IA, Gu W, Kim KA, Jeong JJ, Jang SE, Kim DH (2013) Arctigenin ameliorates inflammation in vitro and in vivo by inhibiting the PI3K/AKT pathway and polarizing M1 macrophages to M2-like macrophages. Eur J Pharmacol 708(1–3):21–29
Imenshahidi M, Hosseinzadeh H (2019) Berberine and barberry (Berberis vulgaris): a clinical review. Phytother Res 33(3):504–523
Isidro RA, Appleyard CB (2016) Colonic macrophage polarization in homeostasis, inflammation, and cancer. Am J Physiol Gastrointest Liver Physiol 311(1):G59–G73
Isidro RA, Bonilla FJ, Pagan H, Cruz ML, Lopez P, Godoy L, Yamamura Y (2014) The probiotic mixture VSL#3 alters the morphology and secretion profile of both polarized and unpolarized human macrophages in a polarization-dependent manner. J Clin Cell Immunol 5(3):1000227. https://doi.org/10.4172/2155-9899.1000227
Jang SE, Hyam S, Han M, Kim SY, Lee BG, Kim DH (2013) Lactobacillus brevis G-101 ameliorates colitis in mice by inhibiting NF-κB, MAPK and AKT pathways and by polarizing M1 macrophages to M2-like macrophages. J Appl Microbiol 115(3):888–896
Jang SE, Han MJ, Kim SY, Kim DH (2014) Lactobacillus plantarum CLP-0611 ameliorates colitis in mice by polarizing M1 to M2-like macrophages. Int Immunopharmacol 21(1):186–192
Jang HM, Kang GD, Van Le TK, Lim SM, Jang DS, Kim DH (2017) 4-Methoxylonchocarpin attenuates inflammation by inhibiting lipopolysaccharide binding to Toll-like receptor of macrophages and M1 macrophage polarization. Int Immunopharmacol 45:90–97
Koelink PJ, Bloemendaal FM, Li B, Westera L, Vogels EW, van Roest M, Gloudemans AK, van Wout AB, Korf H, Vermeire S, te Velde AA (2019) Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling. Gut. https://doi.org/10.1136/gutjnl-2019-318264
Krausgruber T, Blazek K, Smallie T, Lockstone H, Sahgal N, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M, Udalova IA (2011) IRF5 promotes inflammatory macrophage polarization and Th1/Th17 response. Nat Immunol 3:231
Kühl AA, Erben U, Kredel LI, Siegmund B (2015) Diversity of intestinal macrophages in inflammatory bowel diseases. Front immunol 6:613. https://doi.org/10.3389/fimmu.2015.00613
Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, Prockop DJ (2009) Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 5(1):54–63
Lee AS, Sung MJ, Kim W, Jung YJ (2018) COMP-angiopoietin-1 ameliorates inflammation-induced lymphangiogenesis in dextran sulfate sodium (DSS)-induced colitis model. J Mol Med 96(5):459–467
Li C, Xi Y, Li S, Zhao Q, Cheng W, Wang Z, Chen G (2015) Berberine ameliorates TNBS induced colitis by inhibiting inflammatory responses and Th1/Th17 differentiation. Mol Immunol 67(2):444–454
Li C, Xu MM, Wang K, Adler AJ, Vella AT, Zhou B (2018a) Macrophage polarization and meta-inflammation. Transl Res 191:29–44
Li J, Chen N, Wang D, Zhang J, Gong X (2018b) Efficacy of vitamin D in treatment of inflammatory bowel disease: A meta-analysis. Medicine. https://doi.org/10.1097/md.0000000000012662
Liang HL, Ouyang Q (2008) A clinical trial of combined use of rosiglitazone and 5-aminosalicylate for ulcerative colitis. World J Gastroenterol 14(1):114–119
Lim SM, Jeong JJ, Kang GD, Kim KA, Choi HS, Kim DH (2015) Timosaponin AIII and its metabolite sarsasapogenin ameliorate colitis in mice by inhibiting NF-κB and MAPK activation and restoring Th17/Treg cell balance. Int Immunopharmacol 25(2):493–503
Lissner D, Schumann M, Batra A, Kredel L-I, Kühl AA, Erben U, May C, Schulzke JD, Siegmund B (2015) Monocyte and M1 macrophage-induced barrier defect contributes to chronic intestinal inflammation in IBD. Inflamm Bowel Dis 21(6):1297–1305
Marinković G, Hamers AA, de Vries CJ, de Waard V (2014) 6-Mercaptopurine reduces macrophage activation and gut epithelium proliferation through inhibition of GTPase Rac1. Inflamm Bowel Dis 20(9):1487–1495
Moeslinger T, Friedl R, Spieckermann PG (2006) Inhibition of inducible nitric oxide synthesis by azathioprine in a macrophage cell line. Life Sci 79(4):374–381
Na YR, Stakenborg M, Seok SH, Matteoli G (2019) Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat Rev Gastroenterol 16:531–543
Nazareth N, Magro F, Silva J, Duro M, Gracio D, Coelho R, Appelberg R, Macedo G, Sarmento A (2014) Infliximab therapy increases the frequency of circulating CD16+ monocytes and modifies macrophage cytokine response to bacterial infection. Clin Exp Immunol 177(3):703–711
Neurath MF (2017) Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol 14(5):269–278
Park HJ, Kim J, Saima FT et al (2018) Adipose-derived stem cells ameliorate colitis by suppression of inflammasome formation and regulation of M1-macrophage population through prostaglandin E2. Biochem Biophys Res Commun 498:988–995
Phatak UP, Alper A, Pashankar DS (2019) Complementary and alternative medicine use in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 68(2):157–160
Qiu P, Liu Y, Zhang J (2018) The role and mechanisms of macrophage autophagy in sepsis. J Inflamm. https://doi.org/10.1007/s10753-018-0890-8
Ruffell D, Mourkioti F, Gambardella A, Kirstetter P, Lopez RG, Rosenthal N, Nerlov C (2009) A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. Proc Natl Acad Sci USA 106(41):17475–17480
Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, Miyake T, Matsushita K, Okazaki T, Saitoh T, Honma K (2010) The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11(10):936–944
Scaldaferri F, Gerardi V, Lopetuso LR, Del Zompo F, Mangiola F, Boškoski I, Bruno G, Petito V, Laterza L, Cammarota G, Gaetani E (2013) Gut microbial flora, prebiotics, and probiotics in IBD: their current usage and utility. Biomed Res. https://doi.org/10.1155/2013/435268
Seo DH, Che X, Kwak MS, Kim S, Kim JH, Ma HW, Kim SW (2017) Interleukin-33 regulates intestinal inflammation by modulating macrophages in inflammatory bowel disease. Sci Rep 7(1):851
Skovdahl H, Damås J, Granlund A, Østvik A, Doseth B, Bruland T, Mollnes T, Sandvik A (2018) CC motif ligand 20 (CCL20) and CC motif chemokine receptor 6 (CCR6) in human peripheral blood mononuclear cells: dysregulated in ulcerative colitis and a potential role for CCL20 in IL-1β release. Int J Mol Sci 19(10):3257. https://doi.org/10.3390/ijms19103257
Song JY, Kang HJ, Hong JS, Kim CJ, Shim JY, Lee CW, Choi J (2017) Umbilical cord-derived mesenchymal stem cell extracts reduce colitis in mice by re-polarizing intestinal macrophages. Sci Rep 7(1):9412. https://doi.org/10.1038/s41598-017-00840-2
Song WJ, Li Q, Ryu MO, Ahn JO, Bhang DH, Jung YC, Youn HY (2018) TSG-6 released from intraperitoneally injected canine adipose tissue-derived mesenchymal stem cells ameliorate inflammatory bowel disease by inducing M2 macrophage switch in mice. Stem Cell Res Ther 9(1):91
Sotillo J, Ferreira I, Potriquet J, Laha T, Navarro S, Loukas A, Mulvenna J (2017) Changes in protein expression after treatment with Ancylostoma caninum excretory/secretory products in a mouse model of colitis. Sci Rep 7:41883. https://doi.org/10.1038/srep41883
Steinbach EC, Plevy SE (2013) The role of macrophages and dendritic cells in the initiation of inflammation in IBD. Inflamm Bowel Dis 20(1):166–175
Swidsinski A, Loening-Baucke V, Bengmark S, Lochs H, Dörffel Y (2007) Azathioprine and mesalazine-induced effects on the mucosal flora in patients with IBD colitis. Inflamm Bowel Dis 13(1):51–56
Tang J, Feng Y, Tsao S, Wang N, Curtain R, Wang Y (2009) Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmacol 126(1):5–17
Taylor KM, Irving PM (2011) Optimization of conventional therapy in patients with IBD. Nat Rev Gastroenterol 8(11):646
Tokuhira N, Kitagishi Y, Suzuki M, Minami A, Nakanishi A, Ono Y, Ogura Y (2015) PI3K/AKT/PTEN pathway as a target for Crohn’s disease therapy. Int J Mol Med 35(1):10–16
Tsai WJ, Chang CT, Wang GJ, Lee TH, Chang SF, Lu SC, Kuo YC (2011) Arctigenin from Arctium lappa inhibits interleukin-2 and interferon gene expression in primary human T lymphocytes. Chin Med 6(1):12. https://doi.org/10.1186/1749-8546-6-12
Vasudevan A, Gibson PR, Van Langenberg DR (2019) Systematic review: cost-effective strategies of optimizing anti-tumor necrosis and immunomodulators in inflammatory bowel disease. Inflamm Bowel Dis. https://doi.org/10.1093/ibd/izy399
Vemulpad S, Jamie J (2014) Arctigenin from arctium lappa inhibits interleukin-2 and interferon gene expression in primary human T lymphocytes recent advances in plant-based, traditional, and natural medicines. Apple Academic Press, Palm Bay, pp 140–157
Vos AC, Wildenberg ME, Duijvestein M, Verhaar AP, van den Brink GR, Hommes DW (2011a) Anti-tumor necrosis factor-α antibodies induce regulatory macrophages in an Fc region-dependent manner. Gastroenterology 140(1):221–230
Vos AC, Wildenberg ME, Arijs I, Duijvestein M, Verhaar AP, De Hertogh G, Vermeire S, Rutgeerts P, van den Brink GR, Hommes DW (2011b) Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro. Inflamm Bowel Dis 18(3):401–408
Wu Z, Boersema GS, Kroese LF, Taha D, Vennix S, Bastiaansen-Jenniskens YM, Peppelenbosch M (2015) Reducing colorectal anastomotic leakage with tissue adhesive in experimental inflammatory bowel disease. Inflamm Bowel Dis 21(5):1038–1046
Yancopoulos GD, Davis S, Gale NW, RudgeJS Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407(6801):242. https://doi.org/10.1038/35025215
You Y, Zhou C, Li D, Cao ZL, Shen W, Li WZ, Shen X (2016) Sorting nexin 10 acting as a novel regulator of macrophage polarization mediates inflammatory response in experimental mouse colitis. Sci Rep 6:20630. https://doi.org/10.1038/srep20630
Yousefi-Ahmadipour A, Rashidian A, Mirzaei MR, Farsinejad A, PourMohammadi-Nejad F, Ghazi-Khansari M, Saremi J (2019) Combination therapy of mesenchymal stromal cells and sulfasalazine attenuates trinitrobenzene sulfonic acid induced colitis in the rat: the S1P pathway. J Cell Physiol 234(7):11078–11091
Zhang X, Xu F, Liu L, Feng L, Wu X, Shen Y, Xu Q (2017) (+)-Borneol improves the efficacy of edaravone against DSS-induced colitis by promoting M2 macrophages polarization via JAK2-STAT3 signaling pathway. Int Immunopharmacol 53:1–10
Zhang H, Dai Y, Liu Y, Wu T, Li J, Wang X, Wang W (2018) Helicobacter pylori colonization protects against chronic experimental colitis by regulating Th17/Treg balance. Inflamm Bowel Dis 24(7):1481–1492
Zhu W, Yu J, Nie Y, Shi X, Liu Y, Li F, Xl Zhang (2014) Disequilibrium of M1 and M2 macrophages correlates with the development of experimental inflammatory bowel diseases. Immunol Invest 43(7):638–652
Zhu W, JinZ YuJ, Liang J, Yang Q, Li F, Zhang X (2016a) Baicalin ameliorates experimental inflammatory bowel disease through polarization of macrophages to an M2 phenotype. Int Immunopharmacol 35:119–126
Zhu Y, Li X, Chen J, Chen T, Shi Z, Lei M, Fei X (2016b) The pentacyclic triterpene Lupeol switches M1 macrophages to M2 and ameliorates experimental inflammatory bowel disease. Int Immunopharmacol 30:74–84
Zhu Y, Zhou J, Feng Y, Chen L, Zhang L, Yang F, Shu C (2018) control of intestinal inflammation, colitis-associated tumorigenesis, and macrophage polarization by fibrinogen-like protein 2. Front Immunol 9:87. https://doi.org/10.3389/fimmu.2018.00087
Zhu X, Zhu Y, Li C, Yu J, Ren D, Qiu S, Zhu W (2019) 1, 25-Dihydroxyvitamin D regulates macrophage polarization and ameliorates experimental inflammatory bowel disease by suppressing miR-125b. Int Immunopharmacol 67:106–118
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Seyedizade, S.S., Afshari, K., Bayat, S. et al. Current Status of M1 and M2 Macrophages Pathway as Drug Targets for Inflammatory Bowel Disease. Arch. Immunol. Ther. Exp. 68, 10 (2020). https://doi.org/10.1007/s00005-020-00576-4
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DOI: https://doi.org/10.1007/s00005-020-00576-4