Innate immune memory: The evolving role of macrophages in therapy
- Department of Microbiology, New York University Grossman School of Medicine, United States
- Perlmutter Cancer Center, New York University Langone Health, United States
Figures
Figure 1
Central and peripheral trained immunity.
A primary stimulus can initiate two complementary training programs. Local (peripheral) training occurs when resident tissue macrophages (resident macrophages RTMs, blue → purple with receptor activation) sense the insult, secrete cytokines, and acquire a trained phenotype within the lung. Central (bone-marrow) training arises when the same stimulus reprograms hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, producing primed monocytes that enter the circulation, migrate to the lung, and differentiate into trained monocyte-derived macrophages (Mo-Macs, red). For clarity, we define central trained innate memory (CTM) as training strictly within HSPCs/myeloid progenitors. Peripheral trained innate memory (PTM) encompasses local training of mature macrophages, including those residing in bone marrow niches. These pathways may act independently or together, depending on the nature, timing, and intensity of the initial insult. Upon re-exposure, whichever trained population is present mounts an enhanced, coordinated response, illustrating that peripheral and central pathways are bona fide and often cooperative forms of innate immune memory. Image generated using BioRender.com.
Figure 2
Triggers of trained immunity across all tissues.
Peripheral and central trained immunity can be initiated by diverse stimuli, including pathogens (viruses, bacteria, fungi, vector-borne agents, and enteric or blood parasites), allergens (food- or environmental-derived), purified microbial or synthetic compounds, vaccines, toxins (radiation, air pollution, cigarette smoke), physiological processes such as aging and pregnancy. Following the primary stimulus, macrophages in mucosal sites (skin, gut, lung), lymphoid organs (spleen, bone marrow, lymph nodes), lymphatic-associated tissues (liver, kidney), and the brain undergo profound epigenetic and metabolic reprogramming. These trained macrophages and the monocytes they give rise to subsequently mount an amplified immune response to secondary challenges, which can be host-protective or host-damaging depending on context. Image generated using BioRender.com.
Figure 3
Trained immunity of macrophages and monocytes in mucosal tissues.
Trained immunity in mucosal tissues is induced by a variety of stimuli causing local programming of tissue-resident macrophages via metabolic and epigenetic reprogramming resulting in long-term changes in macrophages and monocytes. Image generated using BioRender.com.
Figure 4
Trained immunity in microglia and its role in Alzheimer’s Disease.
Lipopolysaccharide (LPS) activates microglial Toll-like receptors (TLRs), triggering the release of C1q, TNF-a, and IL-1a, which activate A1 astrocytes that damage neurons and oligodendrocytes, contributing to Alzheimer’s pathology. LPS-induced ferritinophagy causes an increase in intracellular iron (Fe), leading to ROS production and NLRP3 inflammasome activation, driving chronic inflammation. This inflammatory response may override microglial tolerization, promoting neurodegenerative disease, while reducing training could mitigate neuronal loss. Image generated using BioRender.com.
Figure 5
Consequences of trained immunity- host beneficial and maladaptive.
Trained immunity can be advantageous when enhancing host defense and disease outcomes after vaccination, β-glucan therapy, and viral, bacterial, or fungal infections, and even after exposure to select allergens or pollutants. Yet the same innate memory programs may turn maladaptive, exacerbating graft rejection, promoting atherosclerosis, fueling neurodegeneration, and driving autoimmune conditions such as rheumatoid arthritis. In case of cancer, consequences of trained immunity are context-dependent with leading to host-beneficial or host-detrimental outcomes. Image generated using BioRender.com
Figure 6
Maladaptive consequences of trained immunity in neurovegetative diseases.
In Alzheimer’s disease, trained immunity results in impaired amyloid-β phagocytosis by microglia due to CD33-SHP1/2 signaling, leading to the accumulation of inflammatory cytokines and exacerbation of disease progression. In Parkinson’s disease, the aggregation of α-synuclein activates TLR1/2 receptors on microglia, promoting pro-inflammatory responses that contribute to neurodegeneration. In multiple sclerosis, epigenetic changes, including histone modification and DNA methylation, drive the activation of pro-inflammatory macrophages, further contributing to demyelination and disease progression. The diagram highlights the pathological mechanisms driving these neurodegenerative diseases and underscores the potential role of trained immunity in their progression.
This figure was generated using ChatGPT (GPT-5) on February 10, 2025, and is released under a perpetual, worldwide, royalty-free license permitting unrestricted scientific publication, distribution, and modification.
Tables
Table 1
Summary of trained immunity in lung macrophages.
| Stimulus / Exposure | Macrophage Subset(s) | Training Outcome | Duration / Turnover | Therapeutic / Pathological Implications | Relevant References |
|---|---|---|---|---|---|
| Influenza infection | AMs, Mo-AMs, IMs (incl. NAMs) | Enhanced IFN-γ/IL-1β signaling, metabolic & chromatin remodeling | Weeks; largely BM-derived AM replacement, NAMs expand locally | Protects against secondary bacterial pneumonia; context-dependent (resident vs BM-derived) | Ural et al., 2020; Li et al., 2022b; Aegerter et al., 2020; Banete et al., 2021; Vangeti et al., 2023; Hoeve et al., 2012; Iliakis et al., 2023 |
| SARS-CoV-2 infection | AMs, Mo-AMs | Elevated CXCL10, TNF-α, IL-6 (trained immunity phenotype) | Persistent post-infection; risk of chronic inflammation | Contributes to antiviral defense but may drive post-acute COVID-19 syndromes | Yeung et al., 2025; Winkler et al., 2020; Cvetkovic et al., 2023; Netea et al., 2023; Netea and Joosten, 2023; Arunachalam et al., 2020; Machiels et al., 2018 |
| Helminth infection (e.g., Nb, Sv, Hp) | AMs, Mo-AMs | Type 2 skewing (Arg1⁺, RELMα⁺), tissue repair phenotype | Lasting after infection; Mo-AMs>TR AMs in larvicidal activity | Enhances repair and tolerance; primes CD8⁺ T cells, cross-protection (e.g., SARS-CoV-2) | Aegerter et al., 2020; Chen et al., 2022a; Misharin et al., 2017; Bouchery et al., 2015; Sveiven et al., 2023; Weyand et al., 2017; Marsland et al., 2008; Silveira et al., 2002; Oliveira et al., 2019; Chen et al., 2012 |
| Allergens (HDM) & viral co-infection (MuHV-4) | AMs, Mo-AMs, regulatory monocytes | Regulatory training reduces Th2 priming | Weeks–months | Protective against asthma exacerbations | Lechner et al., 2022 |
| Environmental exposures (e.g., Borrelia, HDM) | Lung macrophages, BM-derived progenitors | Glycolysis-dependent memory-like states; TNF modulation | Variable | Protection vs parasites (Ascaris), but potential for maladaptive inflammation | Cheng et al., 2014 |
| Vaccines (BCG, influenza, COVID-19) | AMs, BM-derived monocytes | Epigenetic & metabolic reprogramming | Months; reinforced by central training | Enhances heterologous protection; may synergize with cancer therapies | Cirovic et al., 2020; Mhlanga et al., 2025; Buffen et al., 2014; Netea et al., 2023; Bulut et al., 2025; Debisarun et al., 2021; Chakraborty et al., 2023; Gu et al., 2023; Principi and Esposito, 2024; Gurfinkel et al., 2004; Jurado et al., 2025 |
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Innate immune memory: The evolving role of macrophages in therapy
eLife 14:e108276.
https://doi.org/10.7554/eLife.108276
