Pathophysiology and Clinical Relevance of Monocytes in Idiopathic Pulmonary Fibrosis: a Narrative Review
Main Article Content
Abstract
Interstitial lung diseases are a heterogeneous group of disorders characterized by variable degrees of inflammation and fibrosis. Idiopathic pulmonary fibrosis (IPF) is one of the most common types of lung fibrosis and is linked to a poor prognosis. Several biomarkers have been developed to help doctors predict early on the disease's course and how well it will respond to treatment. The pathogenesis of fibrotic disease aberrantly implicates monocytes. This process, where monocyte precursors grow in the bone marrow and monocytes move to other tissues, is a lot like alveolar macrophages. CCR2 is the receptor necessary for the classical migration of monocytes to inflamed tissues. This chemokine, monocyte chemoattractant protein 1 (MCP-1, also called CCL2), binds to CCR2 better than any other. Activated monocytes have been found in IPF patients. Patients with activated monocytes can produce profibrotic proteins. Research has linked high blood monocyte counts to the progression of IPF and an increased risk of death.
Downloads
Article Details
Section
This work is licensed under a Creative Commons Attribution 4.0 International License.
How to Cite
References
Maher TM, Bendstrup E, Dron L, Langley J, Smith G, Khalid JM et al. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respir Res 2021;22(1):197. https://doi.org/10.1186/s12931-021-01791-z
Zhu W, Liu C, Tan C, Zhang J. Predictive biomarkers of disease progression in idiopathic pulmonary fibrosis. Heliyon 2023;10(1):e23543. https://doi.org/10.1016/j.heliyon.2023.e23543
Jee AS, Sahhar J, Youssef P, Bleasel J, Adelstein S, Nguyen M et al. Review: Serum biomarkers in idiopathic pulmonary fibrosis and systemic sclerosis associated interstitial lung disease - frontiers and horizons. Pharmacol Ther 2019;202:40-52. https://doi.org/10.1016/j.pharmthera.2019.05.014
Wang Q, Xie Z, Wan N, Yang L, Jin Z, Jin F et al. Potential biomarkers for diagnosis and disease evaluation of idiopathic pulmonary fibrosis. Chin Med J (Engl) 2023;136(11):1278-90. https://doi.org/10.1097/CM9.0000000000002171
Guiot J, Moermans C, Henket M, Corhay JL, Louis R. Blood biomarkers in idiopathic pulmonary fibrosis. Lung 2017;195(3):273-80. https://doi.org/10.1007/s00408-017-9993-5
Ley B, Collard HR, King TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183(4):431-40. https://doi.org/10.1164/rccm.201006-0894CI
Min B, Grant-Orser A, Johannson KA. Peripheral blood monocyte count and outcomes in patients with interstitial lung disease: a systematic review and meta-analysis. Eur Respir Rev 2023;32(169):230072. https://doi.org/10.1183/16000617.0072-2023
Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med 2017;214(8):2387-404. https://doi.org/10.1084/jem.20162152
Phan THG, Paliogiannis P, Nasrallah GK, Giordo R, Eid AH, Fois AG et al. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cell Mol Life Sci 2021;78(5):2031-57. https://doi.org/10.1007/s00018-020-03665-0
She YX, Yu QY, Tang XX. Role of interleukins in the pathogenesis of pulmonary fibrosis. Cell Death Discov 2021;7(1):52 . https://doi.org/10.1038/s41420-021-00426-2
Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003;112(12):1776-84. https://doi.org/10.1172/JCI20530
Tsoutsou PG, Gourgoulianis KI, Petinaki E, Germenis A, Tsoutsou AG, Mpaka M et al. Cytokine levels in the sera of patients with idiopathic pulmonary fibrosis. Respir Med 2006;100(5):938-45. https://doi.org/10.1016/j.rmed.2005.08.010
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002;3(5):349-63. https://doi.org/10.1038/nrm809
Todd NW, Scheraga RG, Galvin JR, Iacono AT, Britt EJ, Luzina IG et al. Lymphocyte aggregates persist and accumulate in the lungs of patients with idiopathic pulmonary fibrosis. J Inflamm Res 2013;6:63-70. https://doi.org/10.2147/JIR.S44170
Moua T, Lee AS, Ryu JH. Comparing effectiveness of prognostic tests in idiopathic pulmonary fibrosis. Expert Rev Respir Med 2019;13(10):993-1004. https://doi.org/10.1080/17476348.2019.1661357
White ES, Xia M, Murray S, Dyal R, Flaherty CM, Flaherty KR et al. Plasma surfactant protein-D, matrix metalloproteinase-7, and osteopontin index distinguishes idiopathic pulmonary fibrosis from other idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2016;194(10):1242-51. https://doi.org/10.1164/rccm.201505-0862OC
Xu X, Chen H, Zhu X, Ma Y, Liu Q, Xue Y et al. S100A9 promotes human lung fibroblast cells activation through receptor for advanced glycation end-product-mediated extracellular-regulated kinase 1/2, mitogen-activated protein-kinase and nuclear factor-κB-dependent pathways. Clin Exp Immunol 2013;173(3):523-35. https://doi.org/10.1111/cei.12118
Papiris SA, Tomos IP, Karakatsani A, Spathis A, Korbila I, Analitis A et al. High levels of IL-6 and IL-8 characterize early-on idiopathic pulmonary fibrosis acute exacerbations. Cytokine 2018;102:168-72. https://doi.org/10.1016/j.cyto.2017.08.019
Fathimath Muneesa M, Shaikh SB, Jeena TM, Bhandary YP. Inflammatory mediators in various molecular pathways involved in the development of pulmonary fibrosis. Int Immunopharmacol. 2021;96:107608. https://doi.org/10.1016/j.intimp.2021.107608
Kayıkçı A, Alatas F, Alatas IO, Yıldırım H, Ozen H. The role of biomarkers in the diagnosis and treatment follow-up of idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 2024;41(2):e2024015. https://doi.org/10.36141/svdld.v41i2.15454
Song JW, Do KH, Jang SJ, Colby TV, Han S, Kim DS. Blood biomarkers MMP-7 and SP-A: predictors of outcome in idiopathic pulmonary fibrosis. Chest 2013;143(5):1422-9. https://doi.org/10.1378/chest.12-1134
Hamai K, Iwamoto H, Ishikawa N, Horimasu Y, Masuda T, Miyamoto S et al. Comparative study of circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as disease markers of idiopathic pulmonary fibrosis. Dis Markers 2016;2016:4759040. https://doi.org/10.1155/2016/4759040
Kalafatis D, Löfdahl A, Näsman P, Dellgren G, Wheelock ÅM, Elowsson-Rendin L et al. Distal lung microenvironment triggers release of mediators recognized as potential systemic biomarkers for idiopathic pulmonary fibrosis. Int J Mol Sci 2021;22(24):13421. https://doi.org/10.3390/ijms222413421
Guiot J, Bondue B, Henket M, Corhay JL, Louis R. Raised serum levels of IGFBP-1 and IGFBP-2 in idiopathic pulmonary fibrosis. BMC Pulm Med 2016;16(1):86. https://doi.org/10.1186/s12890-016-0243-4
Jenkins RG, Cottin V, Nishioka Y, Noth I, White ES, Ittrich C et al. Effects of nintedanib on circulating biomarkers of idiopathic pulmonary fibrosis. ERJ Open Res 2024;10(6):00558-2023. https://doi.org/10.1183/23120541.00558-2023
Koga Y, Motegi M, Ono A, Hachisu Y, Utsugi M, Sunaga N et al. Serum galectin-3 as a biomarker of progression of idiopathic pulmonary fibrosis treated with nintedanib. Respir Investig 2025;63(3):394-8. https://doi.org/10.1016/j.resinv.2024.12.005
Martín-Ventura JL, Blanco-Colio LM, Tuñón J, Muñoz-García B, Madrigal-Matute J, Moreno JA et al. Biomarkers in cardiovascular medicine. Rev Esp Cardiol 2009;62(6):677-88. https://doi.org/10.1016/s1885-5857(09)72232-7
Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 2016;44(3):450-62. https://doi.org/10.1016/j.immuni.2016.02.015
Wang S, Li J, Wu C, Lei Z, Wang T, Huang X et al. Single-cell RNA sequencing reveals monocyte-derived interstitial macrophages with a pro-fibrotic phenotype in bleomycin-induced pulmonary fibrosis. Int J Mol Sci 2024;25(21):11669. https://doi.org/10.3390/ijms252111669
Ghanem M, Justet A, Jaillet M, Vasarmidi E, Boghanim T, Hachem M et al. Identification of FGFR4 as a regulator of myofibroblast differentiation in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2024;327(6):L818-30. https://doi.org/10.1152/ajplung.00184.2023
Teoh AKY, Jo HE, Chambers DC, Symons K, Walters EH, Goh NS et al. Blood monocyte counts as a potential prognostic marker for idiopathic pulmonary fibrosis: analysis from the Australian IPF registry. Eur Respir J 2020;55(4):1901855. https://doi.org/10.1183/13993003.01855-2019
Craig VJ, Zhang L, Hagood JS, Owen CA. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2015;53(5):585-600. https://doi.org/10.1165/rcmb.2015-0020TR
Pilling D, Gomer RH. The development of serum amyloid P as a possible therapeutic. Front Immunol 2018;9:2328. https://doi.org/10.3389/fimmu.2018.02328
Perrot CY, Karampitsakos T, Herazo-Maya JD. Monocytes and macrophages: emerging mechanisms and novel therapeutic targets in pulmonary fibrosis. Am J Physiol Cell Physiol 2023;325(4):C1046-57. https://doi.org/10.1152/ajpcell.00302.2023
Fraser E, Denney L, Antanaviciute A, Blirando K, Vuppusetty C, Zheng Y et al. Multi-modal characterization of monocytes in idiopathic pulmonary fibrosis reveals a primed type I interferon immune phenotype. Front Immunol 2021;12:623430. https://doi.org/10.3389/fimmu.2021.623430
Gibbons MA, MacKinnon AC, Ramachandran P, Dhaliwal K, Duffin R, Phythian-Adams AT et al. Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Am J Respir Crit Care Med 2011;184(5):569-81. https://doi.org/10.1164/rccm.201010-1719OC
Zielonka TM, Zycinska K, Radzikowska E, Filewska M, Bialas B, Obrowski MH et al. Influence of sera from interstitial lung disease patients on angiogenic activity of mononuclear cells. Adv Exp Med Biol 2013;756:139-45. https://doi.org/10.1007/978-94-007-4549-0_18
Hult EM, Gurczynski SJ, O'Dwyer DN, Zemans RL, Rasky A, Wang Y et al. Myeloid- and epithelial-derived heparin-binding epidermal growth factor-like growth factor promotes pulmonary fibrosis. Am J Respir Cell Mol Biol 2022;67(6):641-53. https://doi.org/10.1165/rcmb.2022-0174OC
Rojas J, Salazar J, Martínez MS, Palmar J, Bautista J, Chávez-Castillo M et al. Macrophage heterogeneity and plasticity: impact of macrophage biomarkers on atherosclerosis. Scientifica (Cairo) 2015;2015:851252. https://doi.org/10.1155/2015/851252
Cao Y, Rudrakshala J, Williams R, Rodriguez S, Sorkhdini P, Yang AX et al. CRTH2 mediates profibrotic macrophage differentiation and promotes lung fibrosis. Am J Respir Cell Mol Biol 2022;67(2):201-14. https://doi.org/10.1165/rcmb.2021-0504OC
Larson-Casey JL, Saleem K, Surolia R, Pandey J, Mack M, Antony VB et al. Myeloid heterogeneity mediates acute exacerbations of pulmonary fibrosis. J Immunol 2023;211(11):1714-24. https://doi.org/10.4049/jimmunol.2300053
Joshi N, Watanabe S, Verma R, Jablonski RP, Chen CI, Cheresh P et al. A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF/M-CSFR signalling in monocyte-derived alveolar macrophages. Eur Respir J 2020;55(1):1900646. https://doi.org/10.1183/13993003.00646-2019
Akagawa KS. Functional heterogeneity of colony-stimulating factor-induced human monocyte-derived macrophages. Int J Hematol 2002;76(1):27-34. https://doi.org/10.1007/BF02982715
Huang WC, Sala-Newby GB, Susana A, Johnson JL, Newby AC. Classical macrophage activation up-regulates several matrix metalloproteinases through mitogen activated protein kinases and nuclear factor-κB. PLoS One 2012;7(8):e42507. https://doi.org/10.1371/journal.pone.0042507
Pardo A, Selman M. Role of matrix metalloproteases in idiopathic pulmonary fibrosis. Fibrogenesis Tissue Repair 2012;5(Suppl 1):S9. https://doi.org/10.1186/1755-1536-5-S1-S9
Lin C, Rezaee F, Waasdorp M, Shi K, van der Poll T, Borensztajn K et al. Protease activated receptor-1 regulates macrophage-mediated cellular senescence: a risk for idiopathic pulmonary fibrosis. Oncotarget 2015;6(34):35304-14. https://doi.org/10.18632/oncotarget.6095
Zhang X, Ren Y, Xie B, Ye Q, Ban C, Zhang S et al. Blood monocyte counts as a prognostic biomarker and predictor in Chinese patients with idiopathic pulmonary fibrosis. Front Med (Lausanne) 2022;9:955125. https://doi.org/10.3389/fmed.2022.955125
Kreuter M, Lee JS, Tzouvelekis A, Oldham JM, Molyneaux PL, Weycker D et al. Monocyte count as a prognostic biomarker in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2021;204(1):74-81. https://doi.org/10.1164/rccm.202003-0669OC
Karampitsakos T, Torrisi S, Antoniou K, Manali E, Korbila I, Papaioannou O et al. Increased monocyte count and red cell distribution width as prognostic biomarkers in patients with idiopathic pulmonary fibrosis. Respir Res 2021;22(1):140. https://doi.org/10.1186/s12931-021-01725-9
Kreuter M, Lee JS, Tzouvelekis A, Oldham JM, Molyneaux PL, Weycker D et al. Modified blood cell GAP model as a prognostic biomarker in idiopathic pulmonary fibrosis. ERJ Open Res 2024;10(4):00666-2023. https://doi.org/10.1183/23120541.00666-2023
Coelho DJAB, Sousa C, Jacob M, Novais-Bastos H, Melo N, Mota PC et al. The role of monocyte count on monitoring patients with idiopathic pulmonary fibrosis under antifibrotic treatment. Eur Respir J 2020;56(suppl 64):722. https://doi.org/10.1183/13993003.congress-2020.722
Scott MKD, Quinn K, Li Q, Carroll R, Warsinske H, Vallania F et al. Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: a retrospective, multicentre cohort study. Lancet Respir Med 2019 ;7(6):497-508. https://doi.org/10.1016/S2213-2600(18)30508-3
Bernardinello N, Grisostomi G, Cocconcelli E, Castelli G, Petrarulo S, Biondini D et al. The clinical relevance of lymphocyte to monocyte ratio in patients with Idiopathic Pulmonary Fibrosis (IPF). Respir Med 2022;191:106686. https://doi.org/10.1016/j.rmed.2021.106686
Kawamura K, Ichikado K, Anan K, Yasuda Y, Sekido Y, Suga M et al. Monocyte count and the risk for acute exacerbation of fibrosing interstitial lung disease: A retrospective cohort study. Chron Respir Dis 2020 ;17:1479973120909840. https://doi.org/10.1177/1479973120909840
Tsuneyoshi S, Zaizen Y, Tominaga M, Matama G, Umemoto S, Ohno S et al. Clinical significance of high monocyte counts for the continuous treatment with nintedanib. BMC Pulm Med 2023;23(1):242. https://doi.org/10.1186/s12890-023-02536-y
Perrot CY, Karampitsakos T, Herazo-Maya JD. Monocytes and macrophages: emerging mechanisms and novel therapeutic targets in pulmonary fibrosis. Am J Physiol Cell Physiol 2023;325(4):C1046-C1057. https://doi.org/10.1152/ajpcell.00302.2023
Achaiah A, Rathnapala A, Pereira A, Bothwell H, Dwivedi K, Barker R et al. Monocyte and neutrophil levels are potentially linked to progression to IPF for patients with indeterminate UIP CT pattern. BMJ Open Respir Res 2021;8(1):e000899. https://doi.org/10.1136/bmjresp-2021-000899
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69(3):89-95. https://doi.org/10.1067/mcp.2001