Immunosenescence involves a series of ageing-induced alterations in the immune system and is characterized by two opposing hallmarks: defective immune responses and increased systemic inflammation. The immune system is modulated by intrinsic and extrinsic factors and undergoes profound changes in response to the ageing process. Immune responses are therefore highly age-dependent. Emerging data show that immunosenescence underlies common mechanisms responsible for several age-related diseases and is a plastic state that can be modified and accelerated by non-heritable environmental factors and pharmacological intervention. In the kidney, resident macrophages and fibroblasts are continuously exposed to components of the external environment, and the effects of cellular reprogramming induced by local immune responses, which accumulate with age, might have a role in the increased susceptibility to kidney disease among elderly individuals. Additionally, because chronic kidney disease, especially end-stage renal disease, is often accompanied by immunosenescence, which affects these patients independently of age, and many kidney diseases are strongly age-associated, treatment approaches that target immunosenescence might be particularly clinically relevant.
Ageing affects the composition and function of the immune system and leads to immunosenescence, which is characterized by defective immune responses and increased systemic inflammation (also termed inflammageing).
Inflammageing is maladaptive and results from multiple mechanisms, including aberrant inflammasome activation, microbial dysbiosis, accumulation of senescent cells and primary dysregulation of immune cells.
The causes and consequences of immunosenescence overlap, thus forming a vicious cycle that exacerbates immunosenescence.
Immunosenescence is a risk factor for the development of a wide spectrum of age-related diseases and therefore targeting immunosenescence might represent a novel therapeutic strategy for preventing them.
The immune status of patients with chronic kidney disease mimics that of elderly individuals, which underlies shared clinical characteristics such as an increased risk of infection and atherosclerosis.
The immune system has crucial roles in the pathophysiology of kidney disease and the effects of immunosenescence on kidney diseases are therefore also widespread and substantial.
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Nikolich-Zugich, J. The twilight of immunity: emerging concepts in aging of the immune system. Nat. Immunol. 19, 10–19 (2018).
Goronzy, J. J. & Weyand, C. M. Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 14, 428–436 (2013).
Goronzy, J. J., Li, G., Yang, Z. & Weyand, C. M. The janus head of T cell aging – autoimmunity and immunodeficiency. Front. Immunol. 4, 131 (2013).
Betjes, M. G. Immune cell dysfunction and inflammation in end-stage renal disease. Nat. Rev. Nephrol. 9, 255–265 (2013).
Weyand, C. M., Fujii, H., Shao, L. & Goronzy, J. J. Rejuvenating the immune system in rheumatoid arthritis. Nat. Rev. Rheumatol. 5, 583–588 (2009).
Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).
Davis, M. M., Tato, C. M. & Furman, D. Systems immunology: just getting started. Nat. Immunol. 18, 725–732 (2017).
Franceschi, C. et al. Immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity. Front. Immunol. 8, 982 (2017).
Takaori, K. et al. Severity and frequency of proximal tubule injury determines renal prognosis. J. Am. Soc. Nephrol. 27, 2393–2406 (2016).
Lee, S. et al. Distinct macrophage phenotypes contribute to kidney injury and repair. J. Am. Soc. Nephrol. 22, 317–326 (2011).
Krebs, C. F. et al. Autoimmune renal disease is exacerbated by S1P-receptor-1-dependent intestinal Th17 cell migration to the kidney. Immunity 45, 1078–1092 (2016).
Sato, Y. et al. Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney. JCI Insight 1, e87680 (2016).
Asada, N. et al. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. J. Clin. Invest. 121, 3981–3990 (2011).
Sato, Y. & Yanagita, M. Immune cells and inflammation in AKI to CKD progression. Am. J. Physiol. Renal. Physiol. 315, F1501–F1512 (2018).
He, L. et al. AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms. Kidney Int. 92, 1071–1083 (2017).
Schmitt, R., Marlier, A. & Cantley, L. G. Zag expression during aging suppresses proliferation after kidney injury. J. Am. Soc. Nephrol. 19, 2375–2383 (2008).
Ishani, A. et al. Acute kidney injury increases risk of ESRD among elderly. J. Am. Soc. Nephrol. 20, 223–228 (2009).
Yamamoto, T. et al. Time-dependent dysregulation of autophagy: implications in aging and mitochondrial homeostasis in the kidney proximal tubule. Autophagy 12, 801–813 (2016).
Ferenbach, D. A. & Bonventre, J. V. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat. Rev. Nephrol. 11, 264–276 (2015).
Jennette, J. C. & Nachman, P. H. ANCA glomerulonephritis and vasculitis. Clin. J. Am. Soc. Nephrol. 12, 1680–1691 (2017).
Couser, W. G. Primary membranous nephropathy. Clin. J. Am. Soc. Nephrol. 12, 983–997 (2017).
O’Sullivan, E. D., Hughes, J. & Ferenbach, D. A. Renal aging: causes and consequences. J. Am. Soc. Nephrol. 28, 407–420 (2017).
Schmitt, R. & Melk, A. Molecular mechanisms of renal aging. Kidney Int. 92, 569–579 (2017).
Georgountzou, A. & Papadopoulos, N. G. Postnatal innate immune development: from birth to adulthood. Front. Immunol. 8, 957 (2017).
Akbar, A. N., Henson, S. M. & Lanna, A. Senescence of t lymphocytes: implications for enhancing human immunity. Trends Immunol. 37, 866–876 (2016).
Goronzy, J. J. & Weyand, C. M. Mechanisms underlying T cell ageing. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-019-0180-1 (2019).
Goronzy, J. J. & Weyand, C. M. Successful and maladaptive T cell aging. Immunity 46, 364–378 (2017).
Rubtsova, K., Rubtsov, A. V., Cancro, M. P. & Marrack, P. Age-associated B cells: a T-bet-dependent effector with roles in protective and pathogenic immunity. J. Immunol. 195, 1933–1937 (2015).
Tahir, S. et al. A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production. J. Immunol. 194, 5725–5735 (2015).
Shirakawa, K. et al. Obesity accelerates T cell senescence in murine visceral adipose tissue. J. Clin. Invest. 126, 4626–4639 (2016).
Sakamoto, K. et al. Osteopontin in spontaneous germinal centers inhibits apoptotic cell engulfment and promotes anti-nuclear antibody production in lupus-prone mice. J. Immunol. 197, 2177–2186 (2016).
Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).
Kuwahara, M. et al. The Menin-Bach2 axis is critical for regulating CD4 T-cell senescence and cytokine homeostasis. Nat. Commun. 5, 3555 (2014).
Geering, B., Stoeckle, C., Conus, S. & Simon, H. U. Living and dying for inflammation: neutrophils, eosinophils, basophils. Trends Immunol. 34, 398–409 (2013).
Hoeffel, G. et al. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).
Mowat, A. M., Scott, C. L. & Bain, C. C. Barrier-tissue macrophages: functional adaptation to environmental challenges. Nat. Med. 23, 1258–1270 (2017).
Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).
Munro, D. A. D. & Hughes, J. The origins and functions of tissue-resident macrophages in kidney development. Front. Physiol. 8, 837 (2017).
Montecino-Rodriguez, E. & Dorshkind, K. B-1 B cell development in the fetus and adult. Immunity 36, 13–21 (2012).
Kovtonyuk, L. V., Fritsch, K., Feng, X., Manz, M. G. & Takizawa, H. Inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment. Front. Immunol. 7, 502 (2016).
Masters, A. R., Haynes, L., Su, D. M. & Palmer, D. B. Immune senescence: significance of the stromal microenvironment. Clin. Exp. Immunol. 187, 6–15 (2017).
Chan, G. K. & Duque, G. Age-related bone loss: old bone, new facts. Gerontology 48, 62–71 (2002).
Geiger, H., de Haan, G. & Florian, M. C. The ageing haematopoietic stem cell compartment. Nat. Rev. Immunol. 13, 376–389 (2013).
Young, K. et al. Progressive alterations in multipotent hematopoietic progenitors underlie lymphoid cell loss in aging. J. Exp. Med. 213, 2259–2267 (2016).
Beerman, I. et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc. Natl Acad. Sci. USA 107, 5465–5470 (2010).
Pang, W. W. et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl Acad. Sci. USA 108, 20012–20017 (2011).
Riley, R. L. Impaired B lymphopoiesis in old age: a role for inflammatory B cells? Immunol. Res. 57, 361–369 (2013).
Rossi, D. J. et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc. Natl Acad. Sci. USA 102, 9194–9199 (2005).
Kumar, B. V., Connors, T. J. & Farber, D. L. Human T cell development, localization, and function throughout life. Immunity 48, 202–213 (2018).
Hamazaki, Y., Sekai, M. & Minato, N. Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution. Immunol. Rev. 271, 38–55 (2016).
Palmer, D. B. The effect of age on thymic function. Front. Immunol. 4, 316 (2013).
Shanley, D. P., Aw, D., Manley, N. R. & Palmer, D. B. An evolutionary perspective on the mechanisms of immunosenescence. Trends Immunol. 30, 374–381 (2009).
den Braber, I. et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36, 288–297 (2012).
Goldrath, A. W., Bogatzki, L. Y. & Bevan, M. J. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J. Exp. Med. 192, 557–564 (2000).
Renkema, K. R., Li, G., Wu, A., Smithey, M. J. & Nikolich-Zugich, J. Two separate defects affecting true naive or virtual memory T cell precursors combine to reduce naive T cell responses with aging. J. Immunol. 192, 151–159 (2014).
Rudd, B. D. et al. Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc. Natl Acad. Sci. USA 108, 13694–13699 (2011).
Kato, A., Takaori-Kondo, A., Minato, N. & Hamazaki, Y. CXCR3(high) CD8(+) T cells with naive phenotype and high capacity for IFN-gamma production are generated during homeostatic T-cell proliferation. Eur. J. Immunol. 48, 1663–1678 (2018).
Li, G. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18, 1518–1524 (2012).
Altan-Bonnet, G. & Germain, R. N. Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLOS Biol. 3, e356 (2005).
DiazGranados, C. A. et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N. Engl. J. Med. 371, 635–645 (2014).
Weng, N. P., Akbar, A. N. & Goronzy, J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306–312 (2009).
Lanna, A., Henson, S. M., Escors, D. & Akbar, A. N. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat. Immunol. 15, 965–972 (2014).
Nakajima, T. et al. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation 105, 570–575 (2002).
Broux, B., Markovic-Plese, S., Stinissen, P. & Hellings, N. Pathogenic features of CD4+CD28- T cells in immune disorders. Trends Mol. Med. 18, 446–453 (2012).
Linterman, M. A. How T follicular helper cells and the germinal centre response change with age. Immunol. Cell Biol. 92, 72–79 (2014).
Eaton, S. M., Burns, E. M., Kusser, K., Randall, T. D. & Haynes, L. Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J. Exp. Med. 200, 1613–1622 (2004).
Sage, P. T., Tan, C. L., Freeman, G. J., Haigis, M. & Sharpe, A. H. Defective TFH cell function and increased TFR cells contribute to defective antibody production in aging. Cell Rep. 12, 163–171 (2015).
Uppal, S. S., Verma, S. & Dhot, P. S. Normal values of CD4 and CD8 lymphocyte subsets in healthy indian adults and the effects of sex, age, ethnicity, and smoking. Cytometry B. Clin. Cytom. 52, 32–36 (2003).
Hadrup, S. R. et al. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J. Immunol. 176, 2645–2653 (2006).
Betjes, M. G., Langerak, A. W., van der Spek, A., de Wit, E. A. & Litjens, N. H. Premature aging of circulating T cells in patients with end-stage renal disease. Kidney Int. 80, 208–217 (2011).
George, R. P. et al. Premature T cell senescence in pediatric CKD. J. Am. Soc. Nephrol. 28, 359–367 (2017).
Crepin, T. et al. ATG-induced accelerated immune senescence: clinical implications in renal transplant recipients. Am. J. Transplant. 15, 1028–1038 (2015).
Mueller, S. N. & Germain, R. N. Stromal cell contributions to the homeostasis and functionality of the immune system. Nat. Rev. Immunol. 9, 618–629 (2009).
Chang, J. E. & Turley, S. J. Stromal infrastructure of the lymph node and coordination of immunity. Trends Immunol. 36, 30–39 (2015).
Fletcher, A. L., Acton, S. E. & Knoblich, K. Lymph node fibroblastic reticular cells in health and disease. Nat. Rev. Immunol. 15, 350–361 (2015).
Heesters, B. A., Myers, R. C. & Carroll, M. C. Follicular dendritic cells: dynamic antigen libraries. Nat. Rev. Immunol. 14, 495–504 (2014).
Dong, X. et al. Antigen presentation by dendritic cells in renal lymph nodes is linked to systemic and local injury to the kidney. Kidney Int. 68, 1096–1108 (2005).
Maarouf, O. H. et al. Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing. JCI Insight 3, 20546 (2018).
Brown, F. D. & Turley, S. J. Fibroblastic reticular cells: organization and regulation of the T lymphocyte life cycle. J. Immunol. 194, 1389–1394 (2015).
Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).
Thompson, H. L., Smithey, M. J., Surh, C. D. & Nikolich-Zugich, J. Functional and homeostatic impact of age-related changes in lymph node stroma. Front. Immunol. 8, 706 (2017).
Cremasco, V. et al. B cell homeostasis and follicle confines are governed by fibroblastic reticular cells. Nat. Immunol. 15, 973–981 (2014).
Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).
Mackay, F. & Schneider, P. Cracking the BAFF code. Nat. Rev. Immunol. 9, 491–502 (2009).
Schietinger, A. & Greenberg, P. D. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 35, 51–60 (2014).
Lee, J. W. et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat. Immunol. 8, 181–190 (2007).
Gardner, J. M. et al. Deletional tolerance mediated by extrathymic aire-expressing cells. Science 321, 843–847 (2008).
Becklund, B. R. et al. The aged lymphoid tissue environment fails to support naive T cell homeostasis. Sci. Rep. 6, 30842 (2016).
Richner, J. M. et al. Age-dependent cell trafficking defects in draining lymph nodes impair adaptive immunity and control of west nile virus infection. PLOS Pathog. 11, e1005027 (2015).
Mebius, R. E. & Kraal, G. Structure and function of the spleen. Nat. Rev. Immunol. 5, 606–616 (2005).
Aw, D. et al. Disorganization of the splenic microanatomy in ageing mice. Immunology 148, 92–101 (2016).
Lefebvre, J. S. et al. The aged microenvironment contributes to the age-related functional defects of CD4 T cells in mice. Aging Cell 11, 732–740 (2012).
Nayar, S. et al. Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology. Proc. Natl Acad. Sci. USA 116, 13490–13497 (2019).
Jones, G. W., Hill, D. G. & Jones, S. A. Understanding immune cells in tertiary lymphoid organ development: it is all starting to come together. Front. Immunol. 7, 401 (2016).
Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).
Pipi, E. et al. Tertiary lymphoid structures: autoimmunity goes local. Front. Immunol. 9, 1952 (2018).
Ruddle, N. H. Lymphatic vessels and tertiary lymphoid organs. J. Clin. Invest. 124, 953–959 (2014).
Lehmann-Horn, K., Wang, S. Z., Sagan, S. A., Zamvil, S. S. & von Budingen, H. C. B cell repertoire expansion occurs in meningeal ectopic lymphoid tissue. JCI Insight 1, e87234 (2016).
Cheng, J. et al. Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal. Proc. Natl Acad. Sci. USA 108, 5560–5565 (2011).
van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).
Van de Pavert, S. A. et al. Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. Nat. Immunol. 10, 1193–1199 (2009).
Schulz, O., Hammerschmidt, S. I., Moschovakis, G. L. & Forster, R. Chemokines and chemokine receptors in lymphoid tissue dynamics. Annu. Rev. Immunol. 34, 203–242 (2016).
Luther, S. A., Lopez, T., Bai, W., Hanahan, D. & Cyster, J. G. BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 12, 471–481 (2000).
Luther, S. A. et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J. Immunol. 169, 424–433 (2002).
Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018).
Krabbe, K. S., Pedersen, M. & Bruunsgaard, H. Inflammatory mediators in the elderly. Exp. Gerontol. 39, 687–699 (2004).
Singh, T. & Newman, A. B. Inflammatory markers in population studies of aging. Ageing Res. Rev. 10, 319–329 (2011).
Csiszar, A., Ungvari, Z., Koller, A., Edwards, J. G. & Kaley, G. Aging-induced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J. 17, 1183–1185 (2003).
Adler, A. S. et al. Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev. 21, 3244–3257 (2007).
Salminen, A. et al. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res. Rev. 7, 83–105 (2008).
Franceschi, C. et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92–105 (2007).
Van Den Biggelaar, A. H. et al. Inflammation underlying cardiovascular mortality is a late consequence of evolutionary programming. FASEB J. 18, 1022–1024 (2004).
Giunta, S. Exploring the complex relations between inflammation and aging (inflammaging): anti-inflamm-aging remodelling of inflammaging, from robustness to frailty. Inflamm. Res. 57, 558–563 (2008).
Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018).
Franceschi, C. & Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69 (Suppl. 1), S4–S9 (2014).
Salimi, S. et al. Inflammation and trajectory of renal function in community-dwelling older adults. J. Am. Geriatr. Soc. 66, 804–811 (2018).
Hinojosa, E., Boyd, A. R. & Orihuela, C. J. Age-associated inflammation and toll-like receptor dysfunction prime the lungs for pneumococcal pneumonia. J. Infect. Dis. 200, 546–554 (2009).
Thevaranjan, N. et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21, 455–466 (2017).
Esplin, B. L. et al. Chronic exposure to a TLR ligand injures hematopoietic stem cells. J. Immunol. 186, 5367–5375 (2011).
Shen-Orr, S. S. et al. Defective signaling in the JAK-STAT pathway tracks with chronic inflammation and cardiovascular risk in aging humans. Cell Syst. 3, 374–384.e374 (2016).
Hashimoto, M. et al. Elimination ofp19(ARF)-expressing cells enhances pulmonary function in mice. JCI Insight 1, e87732 (2016).
Baker, D. J. et al. Naturally occurringp16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).
Shaw, A. C., Goldstein, D. R. & Montgomery, R. R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13, 875–887 (2013).
Ziegler-Heitbrock, L. The CD14+ CD16+ blood monocytes: their role in infection and inflammation. J. Leukoc. Biol. 81, 584–592 (2007).
Metcalf, T. U. et al. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell 14, 421–432 (2015).
Hearps, A. C. et al. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11, 867–875 (2012).
Metcalf, T. U. et al. Human monocyte subsets are transcriptionally and functionally altered in aging in response to pattern recognition receptor agonists. J. Immunol. 199, 1405–1417 (2017).
Bowe, B., Xie, Y., Xian, H., Li, T. & Al-Aly, Z. Association between monocyte count and risk of incident CKD and Progression to ESRD. Clin. J. Am. Soc. Nephrol. 12, 603–613 (2017).
Merino, A. et al. Effect of different dialysis modalities on microinflammatory status and endothelial damage. Clin. J. Am. Soc. Nephrol. 5, 227–234 (2010).
Rogers, N. M., Ferenbach, D. A., Isenberg, J. S., Thomson, A. W. & Hughes, J. Dendritic cells and macrophages in the kidney: a spectrum of good and evil. Nat. Rev. Nephrol. 10, 625–643 (2014).
George, J. F., Lever, J. M. & Agarwal, A. Mononuclear phagocyte subpopulations in the mouse kidney. Am. J. Physiol. Renal Physiol. 312, F640–F646 (2017).
Yatim, K. M., Gosto, M., Humar, R., Williams, A. L. & Oberbarnscheidt, M. H. Renal dendritic cells sample blood-borne antigen and guide T-cell migration to the kidney by means of intravascular processes. Kidney Int. 90, 818–827 (2016).
Stamatiades, E. G. et al. Immune monitoring of trans-endothelial transport by kidney-resident macrophages. Cell 166, 991–1003 (2016).
Chalmers, S. A. et al. Macrophage depletion ameliorates nephritis induced by pathogenic antibodies. J. Autoimmun. 57, 42–52 (2015).
Sharp, P. E. et al. FcgammaRIIb on myeloid cells and intrinsic renal cells rather than B cells protects from nephrotoxic nephritis. J. Immunol. 190, 340–348 (2013).
Sawai, C. M. et al. Hematopoietic stem cells are the major source of multilineage hematopoiesis in adult animals. Immunity 45, 597–609 (2016).
Molawi, K. et al. Progressive replacement of embryo-derived cardiac macrophages with age. J. Exp. Med. 211, 2151–2158 (2014).
Bajpai, G. et al. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat. Med. 24, 1234–1245 (2018).
Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).
Ridker, P. M. et al. Inhibition of interleukin-1beta by Canakinumab and cardiovascular outcomes in patients with chronic kidney disease. J. Am. Coll. Cardiol. 71, 2405–2414 (2018).
Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).
Sheng, J., Ruedl, C. & Karjalainen, K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 43, 382–393 (2015).
Lever, J. M. et al. Resident macrophages reprogram toward a developmental state after acute kidney injury. JCI Insight 4, 125503 (2019).
Lin, S. L., Castano, A. P., Nowlin, B. T., Lupher, M. L. Jr. & Duffield, J. S. Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J. Immunol. 183, 6733–6743 (2009).
Heine, G. H. et al. Monocyte subpopulations and cardiovascular risk in chronic kidney disease. Nat. Rev. Nephrol. 8, 362–369 (2012).
Ferenbach, D. A. et al. Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice. Kidney Int. 82, 928–933 (2012).
Guilliams, M. & Scott, C. L. Does niche competition determine the origin of tissue-resident macrophages? Nat. Rev. Immunol. 17, 451–460 (2017).
Berry, M. R. et al. Renal sodium gradient orchestrates a dynamic antibacterial defense zone. Cell 170, 860–874.e819 (2017).
Lin, S. L. et al. Macrophage Wnt7b is critical for kidney repair and regeneration. Proc. Natl Acad. Sci. USA 107, 4194–4199 (2010).
Huen, S. C. et al. GM-CSF promotes macrophage alternative activation after renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 26, 1334–1345 (2015).
Rodwell, G. E. et al. A transcriptional profile of aging in the human kidney. PLOS Biol 2, e427 (2004).
Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).
Anders, H. J. Of inflammasomes and alarmins: IL-1beta and IL-1alpha in kidney disease. J. Am. Soc. Nephrol. 27, 2564–2575 (2016).
Franceschi, C., Garagnani, P., Vitale, G., Capri, M. & Salvioli, S. Inflammaging and ‘Garb-aging’. Trends Endocrinol. Metab. 28, 199–212 (2017).
Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).
Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).
Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).
Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 23, 174–184 (2017).
Youm, Y. H. et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell. Metab. 18, 519–532 (2013).
Youm, Y. H. et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269 (2015).
Ridker, P. M., Rifai, N., Rose, L., Buring, J. E. & Cook, N. R. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N. Engl. J. Med. 347, 1557–1565 (2002).
Iyer, S. S. et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl Acad. Sci. USA 106, 20388–20393 (2009).
Shigeoka, A. A. et al. An inflammasome-independent role for epithelial-expressed Nlrp3 in renal ischemia-reperfusion injury. J. Immunol. 185, 6277–6285 (2010).
Vilaysane, A. et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. J. Am. Soc. Nephrol. 21, 1732–1744 (2010).
Mulay, S. R. et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1beta secretion. J. Clin. Invest. 123, 236–246 (2013).
Ludwig-Portugall, I. et al. An NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice. Kidney Int. 90, 525–539 (2016).
Lau, A. et al. Renal immune surveillance and dipeptidase-1 contribute to contrast-induced acute kidney injury. J. Clin. Invest. 128, 2894–2913 (2018).
Leaf, I. A. et al. Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury. J. Clin. Invest. 127, 321–334 (2017).
Lemos, D. R. et al. Interleukin-1beta activates a MYC-dependent metabolic switch in kidney stromal cells necessary for progressive tubulointerstitial fibrosis. J. Am. Soc. Nephrol. 29, 1690–1705 (2018).
Kundu, P., Blacher, E., Elinav, E. & Pettersson, S. Our gut microbiome: the evolving inner self. Cell 171, 1481–1493 (2017).
Honda, K. & Littman, D. R. The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84 (2016).
Surana, N. K. & Kasper, D. L. Deciphering the tete-a-tete between the microbiota and the immune system. J. Clin. Invest. 124, 4197–4203 (2014).
Gordon, H. A. Morphological and physiological characterization of germfree life. Ann. N. Y. Acad. Sci. 78, 208–220 (1959).
Hill, D. A. et al. Metagenomic analyses reveal antibiotic-induced temporal and spatial changes in intestinal microbiota with associated alterations in immune cell homeostasis. Mucosal Immunol. 3, 148–158 (2010).
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
Kurts, C., Panzer, U., Anders, H. J. & Rees, A. J. The immune system and kidney disease: basic concepts and clinical implications. Nat. Rev. Immunol. 13, 738–753 (2013).
Couser, W. G. Basic and translational concepts of immune-mediated glomerular diseases. J. Am. Soc. Nephrol. 23, 381–399 (2012).
Tomura, M. et al. Monitoring cellular movement in vivo with photoconvertible fluorescence protein “Kaede” transgenic mice. Proc. Natl Acad. Sci. USA 105, 10871–10876 (2008).
Baeyens, A., Fang, V., Chen, C. & Schwab, S. R. Exit strategies: S1P signaling and T cell migration. Trends Immunol. 36, 778–787 (2015).
Gaffen, S. L., Jain, R., Garg, A. V. & Cua, D. J. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14, 585–600 (2014).
Disteldorf, E. M. et al. CXCL5 drives neutrophil recruitment in TH17-mediated GN. J. Am. Soc. Nephrol. 26, 55–66 (2015).
Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017).
Madhur, M. S. et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension 55, 500–507 (2010).
Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).
Norlander, A. E. et al. A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage. JCI Insight 2, 92801 (2017).
Caillon, A. et al. Gammadelta T cells mediate angiotensin II-induced hypertension and vascular injury. Circulation 135, 2155–2162 (2017).
Norlander, A. E., Madhur, M. S. & Harrison, D. G. The immunology of hypertension. J. Exp. Med. 215, 21–33 (2018).
Biagi, E. et al. Gut microbiota and extreme longevity. Curr. Biol. 26, 1480–1485 (2016).
Claesson, M. J. et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–184 (2012).
Anders, H. J., Andersen, K. & Stecher, B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 83, 1010–1016 (2013).
Ramezani, A. et al. Role of the gut microbiome in uremia: a potential therapeutic target. Am. J. Kidney Dis. 67, 483–498 (2016).
Emal, D. et al. Depletion of gut microbiota protects against renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 28, 1450–1461 (2017).
Andrade-Oliveira, V. et al. Gut bacteria products prevent aki induced by ischemia-reperfusion. J. Am. Soc. Nephrol. 26, 1877–1888 (2015).
Nakade, Y. et al. Gut microbiota-derived D-serine protects against acute kidney injury. JCI Insight 3, 97957 (2018).
Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).
Yoshida, K. et al. The transcription factor ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory. Nat. Immunol. 16, 1034–1043 (2015).
Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).
Lau, C. M. & Sun, J. C. The widening spectrum of immunological memory. Curr. Opin. Immunol. 54, 42–49 (2018).
Christ, A. et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162 (2018).
Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).
Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161.e12 (2018).
Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176–190.e19 (2018).
Wendeln, A. C. et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556, 332−338 (2018).
Chambers, M. C. & Schneider, D. S. Pioneering immunology: insect style. Curr. Opin. Immunol. 24, 10–14 (2012).
Welsh, R. M., Che, J. W., Brehm, M. A. & Selin, L. K. Heterologous immunity between viruses. Immunol. Rev. 235, 244–266 (2010).
Bistoni, F. et al. Evidence for macrophage-mediated protection against lethal Candida albicans infection. Infect. Immun. 51, 668–674 (1986).
Aaby, P., Kollmann, T. R. & Benn, C. S. Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges. Nat. Immunol. 15, 895–899 (2014).
Rule, A. D. et al. The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann. Intern. Med. 152, 561–567 (2010).
Kremers, W. K. et al. Distinguishing age-related from disease-related glomerulosclerosis on kidney biopsy: the Aging Kidney Anatomy study. Nephrol. Dial. Transplant. 30, 2034–2039 (2015).
Hommos, M. S. et al. Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment. Kidney Int. 93, 1175–1182 (2017).
Kimura, T. et al. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 22, 902–913 (2011).
Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015).
Nathan, C. & Ding, A. Nonresolving inflammation. Cell 140, 871–882 (2010).
Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J. & van Deursen, J. M. Cellular senescence in renal ageing and disease. Nat. Rev. Nephrol. 13, 77–89 (2017).
Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).
Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).
de Keizer, P. L. The fountain of youth by targeting senescent cells? Trends Mol. Med. 23, 6–17 (2017).
Hernandez-Segura, A., Nehme, J. & Demaria, M. Hallmarks of cellular senescence. Trends Cell. Biol. 28, 436–453 (2018).
Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147 (2017). e16.
Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018).
Jin, H. et al. Epithelial innate immunity mediates tubular cell senescence after kidney injury. JCI Insight 4, 125490 (2019).
Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013).
Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).
Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).
Sato, Y. & Yanagita, M. Resident fibroblasts in the kidney: a major driver of fibrosis and inflammation. Inflamm. Regen. 37, 17 (2017).
Huang, Y. et al. Identification of novel genes associated with renal tertiary lymphoid organ formation in aging mice. PLOS ONE 9, e91850 (2014).
Steinmetz, O. M. et al. Analysis and classification of B-cell infiltrates in lupus and ANCA-associated nephritis. Kidney Int. 74, 448–457 (2008).
Lech, M. & Anders, H. J. The pathogenesis of lupus nephritis. J. Am. Soc. Nephrol. 24, 1357–1366 (2013).
Hwang, J. Y., Randall, T. D. & Silva-Sanchez, A. Inducible bronchus-associated lymphoid tissue: taming inflammation in the lung. Front. Immunol. 7, 258 (2016).
Kivity, S., Agmon-Levin, N., Blank, M. & Shoenfeld, Y. Infections and autoimmunity-friends or foes? Trends Immunol. 30, 409–414 (2009).
Simmons, E. M. et al. Effect of renal transplantation on biomarkers of inflammation and oxidative stress in end-stage renal disease patients. Transplantation 79, 914–919 (2005).
Betjes, M. G., Huisman, M., Weimar, W. & Litjens, N. H. Expansion of cytolytic CD4+CD28- T cells in end-stage renal disease. Kidney Int. 74, 760–767 (2008).
Ulrich, C., Heine, G. H., Gerhart, M. K., Kohler, H. & Girndt, M. Proinflammatory CD14+CD16+ monocytes are associated with subclinical atherosclerosis in renal transplant patients. Am. J. Transplant. 8, 103–110 (2008).
Leins, H. et al. Aged murine hematopoietic stem cells drive aging-associated immune remodeling. Blood 132, 565–576 (2018).
Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 493, 338–345 (2013).
Chen, C., Liu, Y., Liu, Y. & Zheng, P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci. Signal. 2, ra75 (2009).
Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl Med. 6, 268ra179 (2014).
Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl Med. 10, eaaq1564 (2018).
Fourati, S. et al. Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination. Nat. Commun. 7, 10369 (2016).
Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).
Fukushima, Y., Minato, N. & Hattori, M. The impact of senescence-associated T cells on immunosenescence and age-related disorders. Inflamm. Regen. 38, 24 (2018).
The authors’ work is supported by the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP18gm5010002 and JP18gm0610011; as well as grants from the TMK Project, KAKENHI Grant-in-Aid for Scientific Research B (17H04187), Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS), Grant-in-Aid on Innovative Areas (17H05642, 18H04673), Grant-in-Aid for Exploratory Research (17K19677), the Translational Research Program, and the Strategic Promotion for Practical Application of Innovative Medical Technology (TR-SPRINT) from AMED, and grants from the Uehara Memorial Foundation, Takeda Science Foundation, Yukiko Ishibashi Foundation and the Sumitomo Foundation.
Y.S. is employed by the TMK Project. M.Y. receives research grants from Astellas, Chugai, Daiichi Sankyo, Fujiyakuhin, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Nippon Boehringer Ingelheim and Torii.
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- Replicative senescence
Senescence that occurs as a result of repeated cell division, which is accompanied by gradual telomere shortening.
- Premature senescence
Senescence that occurs as a result of various stress stimuli such as DNA damage, oxidative stress and oncogenic insults.
- Induction therapy
Short-term intensive immunosuppressive therapy administered in the perioperative period to reduce the risk of acute allograft rejection.
Degenerative loss of skeletal muscle strength and mass with ageing.
- Kaede mice
Transgenic mice that ubiquitously express the photoconvertible Kaede protein, which permanently changes its fluorescence emission from green to red on photoactivation with near-UV light.
- Heterologous immunity
Previous immunity to one pathogen can alter the outcome of a subsequent infection with a different pathogen by modulating the immune response.
- Exhausted T cells
T cells with impaired effector functions such as cytokine production and cytotoxicity due to chronic antigen stimulation.
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