Abstract
Background
Fibrosis in multiple organs increases with age. Circulating fibrocytes are bone-marrow-derived mesenchymal progenitors that contribute to heart, lung, and kidney fibrosis under the diseased conditions. Whether circulating fibrocytes contribute to aging-related fibrosis is very limited.
Methods and results
We measured the proportion and differentiation of circulating fibrocytes (CD45+/CD34+/collagen I+) from elders (n = 12) and adults (n = 12) using flow cytometry. Differentiated fibrocytes in the culture dishes were isolated and microarray was performed. The percentage of circulating fibrocytes in elders (1.95 ± 0.43%) was comparable to that in the adults (1.71 ± 0.38%). Cultured fibrocytes displayed enhanced potential of differentiation in the elder group (67.91 ± 5.88%) vs the adult group (44.03 ± 7.98%). In addition, expression of fibroblast activation markers and cell migratory ability were also increased in differentiated fibrocytes from elders. Microarray analysis revealed that differentiated fibrocytes from elders expressed high level of interleukin-18 (IL-18) receptor 1 (IL-18R1). Furthermore, we found IL-18 was elevated in the plasma of elders and IL-18/IL-18R1 was shown to promote fibrocyte differentiation.
Conclusion
Circulating fibrocytes from elders had an enhanced capacity to differentiate into myofibroblasts, and might contribute to age-dependent fibrosis. Age-dependent increment of differentiation at least in part arose from their enhanced expression of IL-18R1. Inhibiting fibrocyte differentiation might be useful as an adjuvant treatment to delay the fibrosis process in aging population.
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References
Goldberg EL, Dixit VD. Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev. 2015;265:63–74.
Prakash J, Pinzani M. Fibroblasts and extracellular matrix: targeting and therapeutic tools in fibrosis and cancer. Adv Drug Deliv Rev. 2017;121:1–2.
Lemmer A, VanWagner LB, Ganger D. Assessment of advanced liver fibrosis and the risk for hepatic decompensation in patients with congestive hepatopathy. Hepatology. 2018;68:1633–41.
Espindola MS, Habiel DM, Hogaboam CM. Reply to D’Alessandro-Gabazza et al: risks of treating idiopathic pulmonary fibrosis with a TAM receptor kinase inhibitor. Am J Respir Crit Care Med. 2018;198:971–3.
Valiente-Alandi I, Potter SJ, Salvador AM, Schafer AE, Schips T, Carrillo-Salinas F, et al. Inhibiting fibronectin attenuates fibrosis and improves cardiac function in a model of heart failure. Circulation. 2018;138:1236–52.
Nastase MV, Zeng-Brouwers J, Wygrecka M, Schaefer L. Targeting renal fibrosis: mechanisms and drug delivery systems. Adv Drug Deliv Rev. 2018;129:295–307.
Cieslik KA, Trial J, Carlson S, Taffet GE, Entman ML. Aberrant differentiation of fibroblast progenitors contributes to fibrosis in the aged murine heart: role of elevated circulating insulin levels. FASEB J. 2013;27:1761–71.
Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1:71–81.
Aiba S, Tagami H. Inverse correlation between CD34 expression and proline-4-hydroxylase immunoreactivity on spindle cells noted in hypertrophic scars and keloids. J Cutan Pathol. 1997;24:65–9.
Mathai SK, Gulati M, Peng X, Russell TR, Shaw AC, Rubinowitz AN, et al. Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype. Lab Invest. 2010;90:812–23.
Wang CH, Huang CD, Lin HC, Lee KY, Lin SM, Liu CY, et al. Increased circulating fibrocytes in asthma with chronic airflow obstruction. Am J Respir Crit Care Med. 2008;178:583–91.
Yang L, Scott PG, Giuffre J, Shankowsky HA, Ghahary A, Tredget EE. Peripheral blood fibrocytes from burn patients: identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells. Lab Invest. 2002;82:1183–92.
Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J, et al. Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009;179:588–94.
Sueblinvong V, Neveu WA, Neujahr DC, Mills ST, Rojas M, Roman J, et al. Aging promotes pro-fibrotic matrix production and increases fibrocyte recruitment during acute lung injury. Adv Biosci Biotechnol. 2014;5:19–30.
Liu Y, Niu XH, Yin X, Liu YJ, Han C, Yang J, et al. Elevated circulating fibrocytes is a marker of left atrial fibrosis and recurrence of persistent atrial fibrillation. J Am Heart Assoc. 2018;7:e008083.
Venkatesan B, Valente AJ, Reddy VS, Siwik DA, Chandrasekar B. Resveratrol blocks interleukin-18-EMMPRIN cross-regulation and smooth muscle cell migration. Am J Physiol Heart Circ Physiol. 2009;297:H874–H886886.
Haudek SB, Xia Y, Huebener P, Lee JM, Carlson S, Crawford JR, et al. Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci USA. 2006;103:18284–9.
van Amerongen MJ, Bou-Gharios G, Popa E, van Ark J, Petersen AH, van Dam GM, et al. Bone marrow-derived myofibroblasts contribute functionally to scar formation after myocardial infarction. J Pathol. 2008;214:377–86.
Chu PY, Mariani J, Finch S, McMullen JR, Sadoshima J, Marshall T, et al. Bone marrow-derived cells contribute to fibrosis in the chronically failing heart. Am J Pathol. 2010;176:1735–42.
Pang WW, Schrier SL, Weissman IL. Age-associated changes in human hematopoietic stem cells. Semin Hematol. 2017;54:39–42.
Cieslik KA, Trial J, Entman ML. Mesenchymal stem cell-derived inflammatory fibroblasts promote monocyte transition into myeloid fibroblasts via an IL-6-dependent mechanism in the aging mouse heart. Faseb J. 2015;29:3160–70.
Wawrocki S, Druszczynska M, Kowalewicz-Kulbat M, Rudnicka W. Interleukin 18 (IL-18) as a target for immune intervention. Acta Biochim Pol. 2016;63:59–63.
Liang H, Xu F, Zhang T, Huang J, Guan Q, Wang H, et al. Inhibition of IL-18 reduces renal fibrosis after ischemia-reperfusion. Biomed Pharmacother. 2018;106:879–89.
Dinarello CA. The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol. 2019;15:612–32.
Melzer D, Hurst AJ, Frayling T. Genetic variation and human aging: progress and prospects. J Gerontol A Biol Sci Med Sci. 2007;62:301–7.
Mekli K, Marshall A, Nazroo J, Vanhoutte B, Pendleton N. Genetic variant of Interleukin-18 gene is associated with the frailty index in the english longitudinal study of ageing. Age Ageing. 2015;44:938–42.
Lee AJ, Chen B, Chew MV, Barra NG, Shenouda MM, Nham T, et al. Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection. J Exp Med. 2017;214:1153–67.
Xiao H, Li H, Wang JJ, Zhang JS, Shen J, An XB, et al. IL-18 cleavage triggers cardiac inflammation and fibrosis upon beta-adrenergic insult. Eur Heart J. 2018;39:60–9.
Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.
Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, et al. The origins of age-related proinflammatory state. Blood. 2005;105:2294–9.
Acknowledgements
Yang Liu was supported by grants from Scientific Research Project of Education Department of Liaoning Province (LZ2019017). Ying Zhang was supported by grants from Scientific Research Project of Education Department of Liaoning Province (LZ2019021). Xiao-Hui Niu was supported by Clinical Medical Science and Technology Development Fund of Jiangsu University (JLY20180073).
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YL and YZ designed the research, wrote the paper, and analyzed the data. XN and YX conducted experiments. SY, YC, and LX analyzed the data and contributed to revise the paper. All authors critically reviewed the manuscript for important intellectual content and approved the final version.
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Niu, XH., Xie, YP., Yang, S. et al. IL-18/IL-18R1 promotes circulating fibrocyte differentiation in the aging population. Inflamm. Res. 69, 497–507 (2020). https://doi.org/10.1007/s00011-020-01330-4
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DOI: https://doi.org/10.1007/s00011-020-01330-4