Central trained immunity and its impact on chronic inflammatory and autoimmune diseases

Memory in the immune system (ie, the ability of immune cells to recognize previously encountered pathogens [or other challenges] and respond more rapidly and effectively after reexposure) has historically been credited exclusively to the adaptive arm of immunity. Accumulating evidence in the past decade unequivocally supports the idea that innate immune cells are also capable of recording previous experience, such as exposure to certain inflammatory or infectious stimuli. Unlike the classic immunologic memory, which reflects genetic changes in clonally expanded populations of antigen-specific memory lymphocytes, innate immune memory is epigenetically imprinted and allows the cells to respond more robustly to future challenges with the same or even an irrelevant stimulus (or pathogen)1Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Crossref PubMed Scopus (1298) Google Scholar (Fig 1). Trained immunity (TRIM) is the term used to indicate the enhanced immune response due to memory of a prior challenge.2Hajishengallis G. Netea M.G. Chavakis T. Innate immune memory, trained immunity and nomenclature clarification.Nat Immunol. 2023; 24: 1393-1394Crossref PubMed Scopus (7) Google Scholar Although TRIM and innate immune memory are related terms, they represent distinct entities: innate immune memory is defined as the epigenetically imprinted memory of previous infection or inflammation, whereas TRIM represents a functional consequence of the retained memory. In this respect, the epigenetic adaptations (deposited chromatin marks, such as histone acetylation or methylation, on enhancers and promoters) that are induced during the primary stimulation persist (or are only partially reversed) even after the stimulus has subsided; the cell is thereby in a state of immune preparedness. The latter is largely indistinguishable from the basal or resting state in terms of active transcription. At this "vigilant" or "trained" state, which is associated with transcriptionally inactive but readily accessible chromatin, the cell is poised to respond faster and stronger because the permissive chromatin allows swift recruitment of transcription factors and, in turn, heightened transcription of target genes2Hajishengallis G. Netea M.G. Chavakis T. Innate immune memory, trained immunity and nomenclature clarification.Nat Immunol. 2023; 24: 1393-1394Crossref PubMed Scopus (7) Google Scholar (Fig 1). In other words, the trained cell uses epigenetic changes as a "bookmark" for chromatin accessibility of key transcription factors. Experimental studies in primitive organisms and mammalian animal models, as well as observational and interventional studies in humans, suggest that TRIM has evolved as an adaptive mechanism for enhanced survival potential against reinfection.1Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Crossref PubMed Scopus (1298) Google Scholar The concept of TRIM was initially established in mature myeloid cells.1Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Crossref PubMed Scopus (1298) Google Scholar It was soon realized that induction of TRIM in cells with a limited lifetime (eg, monocytes have a circulating lifespan of only few days) was in conflict with the long-term effects (from several months to >1 year) of TRIM. The discrepancy, therefore, was that TRIM at the organism level persisted much longer than cellular lifespan. This paradox was resolved by pivotal findings that TRIM may be induced not only in mature myeloid cells in the circulation or in peripheral tissues ("peripheral TRIM") but also in long-lived hematopoietic progenitors of these mature cell types in the bone marrow (BM) ("central TRIM").1Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Crossref PubMed Scopus (1298) Google Scholar Induction of central TRIM involves long-term metabolic and epigenetic adaptations that confer a sustained myeloid differentiation bias in hematopoietic stem and progenitor cells (HSPCs).1Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Crossref PubMed Scopus (1298) Google Scholar For instance, the fungal wall–derived β-glucan, a prototypical TRIM agonist, rewires several pathways, including cell proliferation– and cholesterol biosynthesis–related pathways, leading to expansion of myeloid-biased HSPCs. TRIM-associated epigenetic changes in hematopoietic progenitors are also detectable, at least in part, in their progeny, hence implying heritability of epigenetic alterations during cell differentiation. For instance, in the context of β-glucan–induced trained granulopoiesis, type I interferon signaling in granulocyte-monocyte progenitors is associated with a type I interferon-related epigenetic signature in neutrophils.3Kalafati L. Kourtzelis I. Schulte-Schrepping J. Li X. Hatzioannou A. Grinenko T. et al.Innate immune training of granulopoiesis promotes anti-tumor activity.Cell. 2020; 183: 771-785.e12Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar This epigenetically scripted type I interferon signature enables the rechallenged trained neutrophil to prominently upregulate the expression of genes related to reactive oxygen species production and phagocytosis and to display enhanced tumor-killing activity.3Kalafati L. Kourtzelis I. Schulte-Schrepping J. Li X. Hatzioannou A. Grinenko T. et al.Innate immune training of granulopoiesis promotes anti-tumor activity.Cell. 2020; 183: 771-785.e12Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar The epigenetic adaptations in trained HSPCs enhance the accessibility of specific enhancers and promoters involved in myeloid lineage development and inflammation and, therefore, increase the transcription of the respective immune genes after future stimulation, leading to sustained enhancement of myelopoiesis/granulopoiesis.4de Laval B. Maurizio J. Kandalla P.K. Brisou G. Simonnet L. Huber C. et al.C/EBPβ-dependent epigenetic memory induces trained immunity in hematopoietic stem cells.Cell Stem Cell. 2020; 26 (P657-74.E8)Abstract Full Text Full Text PDF Scopus (151) Google Scholar,5Li X. Wang H. Yu X. Saha G. Kalafati L. Ioannidis C. et al.Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.Cell. 2022; 185: 1709-1727.e18Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Importantly, moreover, transplantation of trained long-term hematopoietic stem cells (LT-HSCs) from mice exposed to systemic inflammation (that was resolved at the time of transplantation, as a result of which, myelopoiesis was phenotypically restored to baseline) transmits the epigenetically imprinted myeloid bias to naive recipient mice, which thus display elevated proportions of myeloid cells with enhanced immune responsiveness to future encounters.5Li X. Wang H. Yu X. Saha G. Kalafati L. Ioannidis C. et al.Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.Cell. 2022; 185: 1709-1727.e18Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Despite its protective potential against infections and tumors, central TRIM may also lead to exaggerated myeloid cell responses that foster or aggravate distinct chronic inflammatory disorders. Through maladaptive training of BM progenitors, therefore, central TRIM may constitute a common mechanistic basis for inflammatory comorbidities (Fig 2). Indeed, studies in mice showed that experimental periodontitis, a local oral inflammatory disease that increases systemic inflammation, leads to IL-1 receptor (IL-1R)-mediated maladaptive training of HSPCs, in turn leading to increased susceptibility to experimental arthritis.5Li X. Wang H. Yu X. Saha G. Kalafati L. Ioannidis C. et al.Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.Cell. 2022; 185: 1709-1727.e18Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar This maladaptively trained phenotype is transmissible by transplantation of whole BM or isolated LT-HSCs from periodontitis-trained donors to naive recipients, who thus develop enhanced joint inflammation and pathology when subjected to collagen antibody–induced arthritis (relative to control recipients of untrained BM or LT-HSCs).5Li X. Wang H. Yu X. Saha G. Kalafati L. Ioannidis C. et al.Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.Cell. 2022; 185: 1709-1727.e18Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar It should be noted that besides being induced by external inflammatory and infectious stimuli, TRIM can also be induced by host-derived inflammatory molecules, as in the context of cardiometabolic disorders, where for instance, oxidized low-density lipoprotein was shown to induce training of human monocytes in an IL-1R–dependent manner.6Christ A. Gunther P. Lauterbach M.A.R. Duewell P. Biswas D. Pelka K. et al.Western diet triggers NLRP3-dependent innate immune reprogramming.Cell. 2018; 172: 162-175.e14Abstract Full Text Full Text PDF PubMed Scopus (659) Google Scholar Similarly, experimental myocardial infarction induces maladaptive training of myeloid progenitors, and the trained phenotype can be transferred by BM transplantation to naive apolipoprotein-E deficient (ApoE−/−) mice on a high-fat diet, which compared with similarly treated controls that received untrained BM, exhibit elevated levels of systemic inflammation and atherosclerotic lesions.7Dong Z. Hou L. Luo W. Pan L.-H. Li X. Tan H.-P. et al.Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.Eur Heart J. 2023; 45 (669-84)Google Scholar This myocardial infarction–trained phenotype is associated with increased systemic levels of IL-1β and TNF, although no specific cytokine was causally linked to innate immune training. In the context of cardiometabolic disorders, IL-1R signaling was implicated in maladaptive central TRIM in lipoprotein receptor-deficient (Ldlr−/−) mice fed a Western-type diet.6Christ A. Gunther P. Lauterbach M.A.R. Duewell P. Biswas D. Pelka K. et al.Western diet triggers NLRP3-dependent innate immune reprogramming.Cell. 2018; 172: 162-175.e14Abstract Full Text Full Text PDF PubMed Scopus (659) Google Scholar In these mice, epigenetic and transcriptomic rewiring in granulocyte-monocyte progenitors resulted in their enhanced proliferation and immune responsiveness to secondary stimuli; the trained granulocyte-monocyte progenitor phenotype persisted even after the mice were switched back to a healthy diet, at least for 4 weeks. However, central TRIM induction in response to a Western-type diet failed in similarly treated Ldlr−/− mice that were also NLRP3 deficient and, expectedly, developed reduced atherosclerotic lesions.6Christ A. Gunther P. Lauterbach M.A.R. Duewell P. Biswas D. Pelka K. et al.Western diet triggers NLRP3-dependent innate immune reprogramming.Cell. 2018; 172: 162-175.e14Abstract Full Text Full Text PDF PubMed Scopus (659) Google Scholar Hyperglycemia has also been shown to induce long-lasting metabolic and epigenetic alterations in macrophages and their progenitors in the BM.8Edgar L. Akbar N. Braithwaite A.T. Krausgruber T. Gallart-Ayala H. Bailey J. et al.Hyperglycemia induces trained immunity in macrophages and their precursors and promotes atherosclerosis.Circulation. 2021; 144: 961-982Crossref PubMed Scopus (112) Google Scholar Transplantation of hyperclycemia-trained BM (from streptozotocin-induced diabetic mice) into Ldlr−/− normoglycemic recipients on a Western-type diet causes increased atherosclerotic plaque formation relative to that in controls receiving BM from normoglycemic donors.8Edgar L. Akbar N. Braithwaite A.T. Krausgruber T. Gallart-Ayala H. Bailey J. et al.Hyperglycemia induces trained immunity in macrophages and their precursors and promotes atherosclerosis.Circulation. 2021; 144: 961-982Crossref PubMed Scopus (112) Google Scholar Evidence for maladaptive TRIM signatures has also been obtained in mouse models of different inflammatory and autoimmune diseases, including SLE, systemic sclerosis, experimental autoimmune encephalomyelitis (a model of multiple sclerosis), Alzheimer disease, and Duchenne muscular dystrophy (reviewed in Ziogas et al9Ziogas A. Bruno M. van der Meel R. Mulder W.J.M. Netea M.G. Trained immunity: target for prophylaxis and therapy.Cell Host Microbe. 2023; 31: 1776-1791Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). The induction of central TRIM is well established in humans,1Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Crossref PubMed Scopus (1298) Google Scholar and clinical observational studies suggest that patients with inflammatory and/or autoimmune diseases (eg, cardiovascular disease, rheumatoid arthritis, periodontitis, SLE, cerebral small vessel disease, hyperimmunoglobulin D syndrome) exhibit a maladaptive trained immune phenotype.9Ziogas A. Bruno M. van der Meel R. Mulder W.J.M. Netea M.G. Trained immunity: target for prophylaxis and therapy.Cell Host Microbe. 2023; 31: 1776-1791Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,10Hajishengallis G. Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities.Nat Rev Immunol. 2021; 21: 426-440Crossref PubMed Scopus (586) Google Scholar Long-lived epigenetic immune memory inscripted in BM HSPCs may explain, for instance, why patients with familial hypercholesterolemia continue to harbor hyperresponsive monocytes despite cholesterol-lowering treatment, why patients with successfully treated periodontitis continue to exhibit enhanced immune responsiveness in peripheral blood myeloid cells, and why the risk of cardiovascular disease is not necessarily decreased during clinical remission of rheumatoid arthritis.10Hajishengallis G. Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities.Nat Rev Immunol. 2021; 21: 426-440Crossref PubMed Scopus (586) Google Scholar Similarly, hyperglycemia-induced central TRIM may explain why treatments for reducing glucose are generally ineffective at reducing the risk of cardiovascular complications in diabetes.8Edgar L. Akbar N. Braithwaite A.T. Krausgruber T. Gallart-Ayala H. Bailey J. et al.Hyperglycemia induces trained immunity in macrophages and their precursors and promotes atherosclerosis.Circulation. 2021; 144: 961-982Crossref PubMed Scopus (112) Google Scholar Given the transmissibility of TRIM phenotypes in BM transplantation studies in mice,5Li X. Wang H. Yu X. Saha G. Kalafati L. Ioannidis C. et al.Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.Cell. 2022; 185: 1709-1727.e18Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar,7Dong Z. Hou L. Luo W. Pan L.-H. Li X. Tan H.-P. et al.Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.Eur Heart J. 2023; 45 (669-84)Google Scholar,8Edgar L. Akbar N. Braithwaite A.T. Krausgruber T. Gallart-Ayala H. Bailey J. et al.Hyperglycemia induces trained immunity in macrophages and their precursors and promotes atherosclerosis.Circulation. 2021; 144: 961-982Crossref PubMed Scopus (112) Google Scholar it is reasonable to expect that inflammatory epigenetic memory in the BM of donors may be transmitted to hematopoietic stem cell transplant recipients, who might thereby become more susceptible to inflammatory diseases. Given the reciprocally reinforced interactions between central TRIM and inflammation, the maladaptive training of HSPCs could generate a vicious feedforward loop linking BM and inflammatory comorbidities10Hajishengallis G. Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities.Nat Rev Immunol. 2021; 21: 426-440Crossref PubMed Scopus (586) Google Scholar (Fig 2). Modulation of the potentially harmful effects of maladaptive TRIM could be achieved, at least in principle, by reversing maladaptive metabolic or epigenetic alterations and by blocking TRIM-inducing immunologic pathways, such as the IL-1 pathway that has been experimentally implicated in central TRIM–driven inflammatory pathology.5Li X. Wang H. Yu X. Saha G. Kalafati L. Ioannidis C. et al.Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.Cell. 2022; 185: 1709-1727.e18Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar,6Christ A. Gunther P. Lauterbach M.A.R. Duewell P. Biswas D. Pelka K. et al.Western diet triggers NLRP3-dependent innate immune reprogramming.Cell. 2018; 172: 162-175.e14Abstract Full Text Full Text PDF PubMed Scopus (659) Google Scholar Consistent with the potential effectiveness of such an approach, systemic inhibition of IL-1 in the CANTOS trial for the treatment of atherosclerosis resulted in a reduced incidence of not only cardiovascular events but also several inflammatory comorbidities (reviewed in Hajishengallis and Chavakis10Hajishengallis G. Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities.Nat Rev Immunol. 2021; 21: 426-440Crossref PubMed Scopus (586) Google Scholar). In conclusion, maladaptive innate immune training of HSPCs in the BM appears to represent a shared mechanism for comorbidities that may be amenable to interventions for holistic treatment of multiple inflammatory disorders in human patients. Supported by the National Instituters of Health (grants DE031206 and DE033643 [to G.H.]), the Deutsche Forschungsgemeinschaft (Collaborative Research Centre TRR369, project C03, and Collaborative Research Centre TRR332, project B03 [to T.C.]), the European Research Council (to T.C.), the Exzellenzförderprogramm für etablierte Wissenschaftlerinnen und Wissenschaftler (German Cancer Aid [to T.C.]), and the the Saxon State Ministry of Science, Culture and Tourism- Sonderzuweisung zur Unterstützung profilbestimmender Struktureinheiten der TUD [to T.C.]). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.