Macrophage polarization or repolarization in tuberculosis

Abstract

Tuberculosis caused by Mycobacterium (M.) tuberculosis remains a global public health threat. Over the last few decades, antitubercular research mainly focused on mechanisms of identifying by which activated macrophages can slaughter or the proliferation of M. tuberculosis bacilli prevented in a cell-dependent manner. In this regard, for disease resolution, inflammatory cytokines are very crucial. Here, we demonstrate how macrophages act as the first line of defense against the M. tuberculosis. Studies have revealed a dual role in M. tuberculosis infection played by macrophages. It is worth mentioning that the macrophages are the crucial immune effector and antigen-presenting cells that play the anti-tubercular response, which is the habitat of M. tuberculosis, hence, followed by progressing the disease protecting M. tuberculosis. This dual role can be correlated with the different macrophage polarization statuses, namely, M1 and M2. Herein, we have stated how the several polarization conditions of macrophages are directly linked to the immune responses during host and M. tuberculosis pathogen interactions. We have proposed that macrophage polarization and repolarization are of paramount significance for the anti-tubercular immune response that may involve a sterile cure of the disease. This article summarizes the immune response to M. tuberculosis, the polarization states of macrophages during M. tuberculosis and the repolarization of macrophages by some agents during some diseases including M. tuberculosis, which may be an important factor in the World Health Organization’s target to cure tuberculosis by 2035.

Keywords

Tuberculosis / Macrophage polarization / Effector responses / Antitubercular immune response

References

[1] Carabalí-Isajar ML, Rodríguez-Bejarano OH, Amado T, Patarroyo MA, Izquierdo MA, Lutz JR, et al. Clinical manifestations and immune response to tuberculosis. World J Microbiol Biotechnol 2023; 39: 206.

[2] Chaw L, Jeludin NH, Thu K. Prevalence and risk factors associated with tuberculosis mortality in Brunei Darussalam. Asian Pac J Trop Med 2023; 16(1): 9-15.

[3] Ikrama IH, Zakou AT, Lamini NJ, Osanga C, Dogara AN, Wakili LY, et al. Tuberculosis prevalence and rifampicin resistance among presumptive patients in Nasarawa State: A three-year retrospective study. One Health Bull 2024; 4(1): 25-31. https://www.doi.org/10.4103/ohbl.ohbl_31_23.

[4] Zhang Y, Li S, Liu Q, Long R, Feng J, Qin H, et al. Mycobacterium tuberculosis heat-shock protein 16. 3 induces macrophage M2 polarization through CCRL2/CX3CR1. Inflammation 2020; 43(2): 487-506.

[5] Meier NR, Jacobsen M, Ottenhoff TH, Ritz N. A systematic review on novel Mycobacterium tuberculosis antigens and their discriminatory potential for the diagnosis of latent and active tuberculosis. Front Immunol 2018; 9: 2476.

[6] Huang Z, Luo Q, Guo Y, Chen J, Xiong G, Peng Y, et al. Mycobacterium tuberculosis-induced polarization of human macrophage orchestrates the formation and development of tuberculous granulomas in vitro. PloS One 2015; 10(6): e0129744.

[7] Matucci A, Maggi E, Vultaggio A. Cellular and humoral immune responses during tuberculosis infection: Useful knowledge in the era of biological agents. J Rheumatol Suppl 2014; 91: 17-23.

[8] Hirayama D, Iida T, Nakase H. The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int J Mol Sci 2017; 19(1): 92.

[9] Kroner A, Greenhalgh AD, Zarruk JG, Dos Santos RP, Gaestel M, David S. TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 2014; 83(5): 1098-1116.

[10] Magdalena G, Magdalena D. Biological functions and diagnostic implications of microRNAs in Mycobacterium tuberculosis infection. Asian Pac J Trop Biomed 2022; 12(1): 1-8.

[11] Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: Enabling diversity with identity. Nat Rev Immunol 2011; 11(11): 750-761.

[12] Tomioka H, Tatano Y, Maw WW, Sano C, Kanehiro Y, Shimizu T. Characteristics of suppressor macrophages induced by mycobacterial and protozoal infections in relation to alternatively activated M2 macrophages. Clin Dev Immunol 2012; 2012: 635451.

[13] Rőszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm 2015; 2015: 816460.

[14] Murray PJ. Macrophage polarization. Annu Rev Physiol 2017; 79: 541566.

[15] Canton J. Phagosome maturation in polarized macrophages. J Leukoc Biol 2014; 96(5): 729-738.

[16] Chistiakov DA, Bobryshev YV, Nikiforov NG, Elizova NV, Sobenin IA, Orekhov AN. RETRACTED: Macrophage phenotypic plasticity in atherosclerosis: The associated features and the peculiarities of the expression of inflammatory genes. Int J Cardiol 2015; 184: 436-445.

[17] Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 2004; 25(12): 677-686.

[18] Sica A, Mantovani A. Macrophage plasticity and polarization: In vivo veritas. J Clin Invest 2012; 122(3): 787-795.

[19] Atri C, Guerfali FZ, Laouini D. Role of human macrophage polarization in inflammation during infectious diseases. Int J Mol Sci 2018; 19(6): 1801.

[20] Lampiasi N, Russo R, Zito F. The alternative faces of macrophage generate osteoclasts. Biomed Res Int 2016; 2016: 9089610.

[21] Porta C, Riboldi E, Ippolito A, Sica A. Molecular and epigenetic basis of macrophage polarized activation. Semin Immunol 2015; 27(4): 237-248.

[22] Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage M1-M2 polarization balance. Front Immunol 2014; 5: 614.

[23] Weisser SB, McLarren KW, Kuroda E, Sly LM. Generation and characterization of murine alternatively activated macrophages. Methods Mol Biol 2013; 946: 225-239.

[24] Malyshev I, Malyshev Y. Current concept and update of the macrophage plasticity concept: Intracellular mechanisms of reprogramming and M3 macrophage “switch” phenotype. Biomed Res Int 2015; 2015: 341308.

[25] O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010; 327(5969): 1098-1102.

[26] Chen M, Divangahi M, Gan H, Shin DS, Hong S, Lee DM, et al. Lipid mediators in innate immunity against tuberculosis: Opposing roles of PGE2 and LXA4 in the induction of macrophage death. J Exp Med 2008; 205(12): 2791-2801.

[27] Gordon S, Martinez FO. Alternative activation of macrophages: Mechanism and functions. Immunity 2010; 32(5): 593-604.

[28] Mulder R, Banete A, Basta S. Spleen-derived macrophages are readily polarized into classically activated (M1) or alternatively activated (M2) states. Immunobiology 2014; 219(10): 737-745.

[29] Xuan W, Qu Q, Zheng B, Xiong S, Fan GH. The chemotaxis of M1 and M2 macrophages is regulated by different chemokines. J Leukoc Biol 2015; 97(1): 61-69.

[30] Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000 Prime Rep 2014; 6: 13.

[31] Jablonski KA, Amici SA, Webb LM, Ruiz-Rosado JD, Popovich PG, Partida-Sanchez S, et al. Novel markers to delineate murine M1 and M2 macrophages. PLoS One 2015; 10(12): e0145342.

[32] O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol 2016; 16(9): 553-565.

[33] Davis JM, Ramakrishnan L. The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 2009; 136(1): 37-49.

[34] Volkman HE, Pozos TC, Zheng J, Davis JM, Rawls JF, Ramakrishnan L. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 2010; 327(5964): 466-469.

[35] Khabibullina NF, Kutuzova DM, Burmistrova IA, Lyadova IV. The biological and clinical aspects of a latent tuberculosis infection. Trop Med Infect Dis 2022; 7(3): 48.

[36] Quintana-Murci L, Alcaïs A, Abel L, Casanova JL. Immunology in natura: Clinical, epidemiological and evolutionary genetics of infectious diseases. Nat Immunol 2007; 8(11): 1165-1171.

[37] Diatlova A, Linkova N, Lavrova A, Zinchenko Y, Medvedev D, Krasichkov A, et al. Molecular markers of early immune response in tuberculosis: Prospects of application in predictive medicine. Int J Mol Sci 2023; 24(17): 13261.

[38] Ehrt S, Schnappinger D, Bekiranov S, Drenkow J, Shi S, Gingeras TR, et al. Reprogramming of the macrophage transcriptome in response to interferon-γ and Mycobacterium tuberculosis: Signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J Exp Med 2001; 194(8): 11231140.

[39] Bhat KH, Yaseen I. Mycobacterium tuberculosis: Macrophage takeover and modulation of innate effector responses. In: Mycobacterium-research and development. London: IntechOpen; 2018. http://dx.doi.org/10.5772/intechopen.75003

[40] Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol 2008; 181(6): 3733-3739.

[41] Ning Y, Wang W, Jordan PM, Barth SA, Hofstetter RK, Xu J, et al. Mycobacterium tuberculosis-Induced prostaglandin J2 and 15-deoxy-prostaglandin J2 inhibit inflammatory signals in human M1 macrophages via a negative feedback loop. J Immunol 2023; 210(10): 1564-1575.

[42] Redente EF, Higgins DM, Dwyer-Nield LD, Orme IM, Gonzalez-Juarrero M, Malkinson AM. Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation. J Leukoc Biol 2010; 88(1): 159-168.

[43] Marino S, Cilfone NA, Mattila JT, Linderman JJ, Flynn JL, Kirschner DE. Macrophage polarization drives granuloma outcome during Mycobacterium tuberculosis infection. Infect Immun 2015; 83(1): 324-338.

[44] Li Z, Lu G, Meng G. Pathogenic fungal infection in the lung. Front Immunol 2019; 10: 1524.

[45] Raju B, Hoshino Y, Belitskaya-Lévy I, Dawson R, Ress S, Gold JA, et al. Gene expression profiles of bronchoalveolar cells in pulmonary TB. Tuberculosis (Edinb) 2008; 88(1): 39-51.

[46] Scriba TJ, Coussens AK, Fletcher HA. Human immunology of tuberculosis. Microbiol Spectr 2017; 5(1). doi:10.1128/microbiolspec.

[47] Harris J, De Haro SA, Master SS, Keane J, Roberts EA, Delgado M, et al. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity 2007; 27(3): 505-517.

[48] Khan A, Zhang K, Singh VK, Mishra A, Kachroo P, Bing T, et al. Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis. Commun Biol 2022; 5(1): 480.

[49] Ly LH, Russell MI, McMurray DN. Microdissection of the cytokine milieu of pulmonary granulomas from tuberculous guinea pigs. Cell Microbiol 2007; 9(5): 1127-1136.

[50] Dorhoi A, Reece ST, Kaufmann SH. For better or for worse: The immune response against Mycobacterium tuberculosis balances pathology and protection. Immunol Rev 2011; 240(1): 235-251.

[51] McClean CM, Tobin DM. Macrophage form, function, and phenotype in mycobacterial infection: Lessons from tuberculosis and other diseases. FEMS Pathog Dis 2016; 74(7): ftw068.

[52] Cadena AM, Flynn JL, Fortune SM. The importance of first impressions: Early events in Mycobacterium tuberculosis infection influence outcome. mBio 2016; 7(2): e00342-16.

[53] Killick KE, Ní Cheallaigh C, O'Farrelly C, Hokamp K, MacHugh DE, Harris J. Receptor-mediated recognition of mycobacterial pathogens. Cell Microbiol 2013; 15(9): 1484-1495.

[54] Cappelli G, Volpe P, Sanduzzi A, Sacchi A, Colizzi V, Mariani F. Human macrophage gamma interferon decreases gene expression but not replication of Mycobacterium tuberculosis: Analysis of the host-pathogen reciprocal influence on transcription in a comparison of strains H37Rv and CMT97. Infect Immun 2001; 69(12): 7262-7270.

[55] Lastrucci C, Bénard A, Balboa L, Pingris K, Souriant S, Poincloux R, et al. Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis. Cell Res 2015; 25(12): 1333-1351.

[56] Lopes RL, Borges TJ, Zanin RF, Bonorino C. IL-10 is required for polarization of macrophages to M2-like phenotype by mycobacterial DnaK (heat shock protein 70). Cytokine 2016; 85: 123-129.

[57] Khan A, Hunter RL, Jagannath C. Emerging role of mesenchymal stem cells during tuberculosis: The fifth element in cell mediated immunity. Tuberculosis (Edinb) 2016; 101S: S45-S52.

[58] Feng Y, Dorhoi A, Mollenkopf HJ, Yin H, Dong Z, Mao L, et al. Platelets direct monocyte differentiation into epithelioid-like multinucleated giant foam cells with suppressive capacity upon mycobacterial stimulation. J infect Dis 2014; 210(11): 1700-1710.

[59] Singh V, Kaur C, Chaudhary VK, Rao KV, Chatterjee S.M. tuberculosis secretory protein ESAT-6 induces metabolic flux perturbations to drive foamy macrophage differentiation. Sci Rep 2015; 5: 12906.

[60] Ravesloot-Chávez MM, Van Dis E, Stanley SA. The innate immune response to Mycobacterium tuberculosis infection. Annu Rev Immunol 2021; 39: 611-637.

[61] Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A. TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 2005; 202(12): 1715-1724.

[62] Feng CG, Scanga CA, Collazo-Custodio CM, Cheever AW, Hieny S, Caspar P, et al. Mice lacking myeloid differentiation factor 88 display profound defects in host resistance and immune responses to Mycobacterium avium infection not exhibited by Toll-like receptor 2 (TLR2)-and TLR4-deficient animals. J Immunol 2003; 171(9): 47584764.

[63] Reiling N, Holscher C, Fehrenbach A, Kroger S, Kirschning CJ, Goyert S, et al. Cutting edge: Toll-like receptor (TLR) 2-and TLR4-mediated pathogen recognition in resistance to airborne infection with Mycobacterium tuberculosis. J Immunol 2002; 169(7): 3480-3484.

[64] Sugawara I, Yamada H, Li C, Mizuno S, Takeuchi O, Akira S. Mycobacterial infection in TLR2 and TLR6 knockout mice. Microbiol Immunol 2003; 47(5): 327-336.

[65] Heitmann L, Schoenen H, Ehlers S, Lang R, Hölscher C. Mincle is not essential for controlling Mycobacterium tuberculosis infection. Immunobiology 2013; 218(4): 506-516.

[66] Marakalala MJ, Guler R, Matika L, Murray G, Jacobs M, Brombacher F, et al. The Syk/CARD9-coupled receptor Dectin-1 is not required for host resistance to Mycobacterium tuberculosis in mice. Microbes Infect 2011; 13(2): 198-201.

[67] Coulombe F, Divangahi M, Veyrier F, de Léséleuc L, Gleason JL, Yang Y, et al. Increased NOD2-mediated recognition of N-glycolyl muramyl dipeptide. J Exp Med 2009; 206(8): 1709-1716.

[68] Juárez E, Carranza C, Hernández-Sánchez F, León-Contreras JC, Hernández-Pando R, Escobedo D, et al. NOD 2 enhances the innate response of alveolar macrophages to Mycobacterium tuberculosis in humans. Eur J Immunol 2012; 42(4): 880-889.

[69] Pandey AK, Yang Y, Jiang Z, Fortune SM, Coulombe F, Behr MA, et al. NOD2, RIP2 and IRF5 play a critical role in the type I interferon response to Mycobacterium tuberculosis. PLoS Pathog 2009; 5(7): e1000500.

[70] Divangahi M, Mostowy S, Coulombe F, Kozak R, Guillot L, Veyrier F, et al. NOD2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity. J Immunol 2008; 181(10): 7157-7165.

[71] Collins AC, Cai H, Li T, Franco LH, Li XD, Nair VR, et al. Cyclic GMP-AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis. Cell Host Microbe 2015; 17(6): 820-828.

[72] Wassermann R, Gulen MF, Sala C, Perin SG, Lou Y, Rybniker J, et al. Mycobacterium tuberculosis differentially activates cGAS-and inflammasome-dependent intracellular immune responses through ESX-1. Cell Host Microbe 2015; 17(6): 799-810.

[73] Watson RO, Bell SL, MacDuff DA, Kimmey JM, Diner EJ, Olivas J, et al. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe 2015; 17(6): 811-819.

[74] Dey B, Dey RJ, Cheung LS, Pokkali S, Guo H, Lee JH, et al. A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis. Nat Med 2015; 21(4): 401-406.

[75] Sia JK, Rengarajan J. Immunology of Mycobacterium tuberculosis infections. Microbiol Spectr 2019; 7(4): 10.1128.

[76] De Martino M, Lodi L, Galli L, Chiappini E. Immune response to Mycobacterium tuberculosis: A narrative review. Front Pediatr 2019; 7: 350.

[77] Ha SH, Choi H, Park JY, Abekura F, Lee YC, Kim JR, et al. Mycobacterium tuberculosis-secreted protein, ESAT-6, inhibits lipopolysaccharide-induced MMP-9 expression and inflammation through NF-κB and MAPK signaling in raw 264. 7 macrophage cells. Inflammation 2020; 43(1): 54-65.

[78] Refai A, Gritli S, Barbouche MR, Essafi M. Mycobacterium tuberculosis virulent factor ESAT-6 drives macrophage differentiation toward the proinflammatory M1 phenotype and subsequently switches it to the antiinflammatory M2 phenotype. Front Cell Infect Microbiol 2018; 8: 327.

[79] Wang S, Zhang J, Sui L, Xu H, Piao Q, Liu Y, et al. Antibiotics induce polarization of pleural macrophages to M2-like phenotype in patients with tuberculous pleuritis. Sci Rep 2017; 7(1): 14982.

[80] Kivimäki K, Leppänen T, Hämäläinen M, Vuolteenaho K, Moilanen E. Pinosylvin shifts macrophage polarization to support resolution of inflammation. Molecules 2021; 26(9): 2772.

[81] Langlais D, Cencic R, Moradin N, Kennedy JM, Ayi K, Brown LE, et al. Rocaglates as dual-targeting agents for experimental cerebral malaria. Proc Natl Acad Sci USA 2018; 115(10): E2366-E2375.

[82] Chatterjee S, Yabaji SM, Rukhlenko OS, Bhattacharya B, Waligurski E, Vallavoju N, et al. Channeling macrophage polarization by rocaglates increases macrophage resistance to Mycobacterium tuberculosis. iScience 2021; 24(8): 102845.

[83] Jayaraman A, Srinivasan S, Kar A, Harish BS, Raja MR, Uppuluri KB, et al. Oceanimonas sp. BPMS22-derived protein protease inhibitor induces anti-leishmanial immune responses through macrophage M2 to M1 repolarization. Int Immunopharmacol 2022; 112: 109281.

[84] Lin F, Shan W, Zheng Y, Pan L, Zuo Z. Toll-like receptor 2 activation and up-regulation by high mobility group box-1 contribute to post-operative neuroinflammation and cognitive dysfunction in mice. J Neurochem 2021; 158(2): 328-341.

[85] Tian J, Song T, Wang H, Wang W, Ma X, Hu Y. Toll-like receptor 2 antagonist ameliorates type 2 diabetes mellitus associated neuropathic pain by repolarizing pro-inflammatory macrophages. Neurochem Res 2021; 46(9): 2276-2284.

[86] Cheng CC, Yang WY, Hsiao MC, Lin KH, Lee HW, Yuh CH. Transcriptomically revealed oligo-fucoidan enhances the immune system and protects hepatocytes via the ASGPR/STAT3/HNF4A axis. Biomolecules 2020; 10(6): 898.

[87] Chen LM, Tseng HY, Chen YA, Al Haq AT, Hwang PA, Hsu HL. Oligo-fucoidan prevents M2 macrophage differentiation and HCT116 tumor progression. Cancers (Basel) 2020; 12(2): 421.

[88] Kou L, Huang H, Tang Y, Sun M, Li Y, Wu J, et al. Opsonized nanoparticles target and regulate macrophage polarization for osteoarthritis therapy: A trapping strategy. J Control Release 2022; 347: 237-255.

[89] Jiménez I, Carabia J, Bobillo S, Palacio C, Abrisqueta P, Pagès C, et al. Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition. J Neurooncol 2020; 149(1): 13-25.