Resident memory macrophages and trained innate immunity at barrier tissues

Over the past decade or so, there has been a significant expansion in our knowledge of innate immune memory and trained innate immunity (TII) (Netea et al., 2016). Although the phrases innate immune memory and TII are often interchangeably used in literature, it is our view that to avoid confusion and given its functional connotation, we should reserve the use of TII only for when we refer to innate immune protective outcomes following induction of innate immune memory. Innate immune memory represents the adaptive state of innate immune cells, including myeloid and lymphoid innate cells, as well as structural barrier cells, that persists long after previous immunological exposure (Domínguez-Andrés et al., 2023; Xing et al., 2020). Such imprinted or trained innate cells lead to an altered, either strengthened or weakened, innate immune response upon subsequent homologous or heterologous immunological exposure. While the strengthened innate immune response often functionally offers enhanced innate immune protection or TII against pathogens or tumor cells (Domínguez-Andrés et al., 2023), it may underpin the maladaptive consequences of inflammatory conditions (Halper-Stromberg and Jabri, 2022). Innate immune memory is sometimes referred to as inflammatory memory (Ordovas-Montanes et al., 2020), and the process of its development is considered to be ‘inflammatory adaptation’ (Niec et al., 2021). Epigenetic modifications and metabolic rewiring are involved in the development and maintenance of innate immune memory (Ferreira et al., 2024; Sun and Barreiro, 2020). However, the short-term activation or temporary epigenetic modifications should not be confused with the persisting epigenetic changes characteristic of bona fide innate immune memory (Sun and Barreiro, 2020). Thus, the time from the acute immunological episode and whether the initial inflammation or infection has resolved are among important considerations for investigating innate immune memory and TII (Niec et al., 2021).

In general, innate immune memory and associated TII can be either centrally or locally induced (Ferreira et al., 2024; Netea and Joosten, 2018; Figure 1). The former often occurs following a systemic immunological event and the training of hematopoietic progenitor cells in the bone marrow and subsequent egress of trained mature myeloid cells such as monocytes and neutrophils into the bloodstream. Such trained circulating myeloid cells may be recruited into the tissue sites in response to locally produced chemotactic signals, thus contributing to TII (Domínguez-Andrés et al., 2023; Kaufmann et al., 2022; Kaufmann et al., 2018). On the other hand, the innate immune memory can arise locally in tissue-resident innate immune cell populations, including macrophages, resulting from a local immunological event (Afkhami et al., 2022; Yao et al., 2018). Recent evidence suggests that tissue-resident memory macrophages could be induced and maintained independently of the recruited blood-derived monocytes (Kang et al., 2024a; Yao et al., 2018). In instances where tissue-resident macrophage populations are largely depleted following an acute episode of infection, the recruited monocytes may adopt a trained phenotype, eventually differentiating to be the tissue-resident memory macrophages but still harboring monocytic gene signatures (Aegerter et al., 2022; Guilliams and Svedberg, 2021). Furthermore, the latest data indicates that locally induced tissue-resident innate immune memory, memory macrophages, or TII could arise in response to a systemic immunological alert or distally derived immunological signals, including gut microbial metabolites (Hoyer et al., 2019; Jeyanathan et al., 2022b; Kang et al., 2024b; Li et al., 2022b; Ngo et al., 2024; Simats et al., 2024). Recent research has demonstrated the remarkable capacity of various tissue sites to accommodate locally elicited tissue-resident innate and adaptive immune memory cells even following successive immunological exposures (Wijeyesinghe et al., 2021). It is of importance to keep in mind that tissue-resident TII may not always be associated with universally enhanced innate immune protection against heterologous pathogens. Mounting evidence suggests that depending on the nature of the heterologous pathogen, there are three likely innate immune outcomes: reduced microbial counts/infection and tissue immunopathology, restrained tissue immunopathology without significant changes in microbial counts/infection, and limited protection in both infection and tissue immunopathology. The second outcome is often seen following acute heterologous respiratory viral infection in the lung and is attributed to enhanced disease tolerance (King and Divangahi, 2019; McCarville and Ayres, 2018). Disease tolerance enhanced through TII or mediated by other mechanisms leads to improved survival of the host via limiting tissue inflammation and injury without altering the magnitude of infection (Afkhami et al., 2022; Damjanovic et al., 2012; Nahrendorf et al., 2021; Pernet et al., 2019). One cannot confuse disease tolerance with innate immune tolerance or weakened innate immune responses rendered by a different type of innate immune memory, upon subsequent homologous or heterologous immunological exposure. Innate immune tolerance often leads to not only heightened magnitude of infection but also excessive tissue immunopathology and injury. For instance, the hosts that have just recovered from acute influenza are especially susceptible to unrestrained bacterial superinfection and immunopathology in the lung (Damjanovic et al., 2013; Small et al., 2010). A firm grasp of differential innate immune protective outcomes by tissue-resident TII is critical to understanding the mechanisms of protection and developing tailored vaccine and immunotherapeutic strategies.

Figure 1

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In the present review, we will focus on the progress being made over the past decade in resident memory macrophages and associated TII at selected barrier tissues, including the lung, skin, gut, and peritoneal cavity. Additionally, a brief section is provided in the end to discuss the evidence demonstrating nonimmune epithelial cell-associated TII at barrier tissues. Like other emerging immunological fields, the ongoing progress raises many more questions. We have confidence that the next decade will witness much more accelerated progress and usher in new vaccine and immunotherapeutic strategies into the clinical pipelines.

Innate immune memory may arise, following local immunological exposure, in tissue-resident macrophages within mucosal tissues, specifically the lung (Afkhami et al., 2022; Kang et al., 2024a; Yao et al., 2018). Indeed, recent studies have shown that local immunological exposure can induce innate immune memory in lung tissue-resident macrophages, a phenomenon known as local training, characterized by heightened MHCII expression, increased production of the proinflammatory cytokines IL-6, TNF, and IL-1β, enhanced phagocytic capacity, increased glycolysis, and protection against heterologous infections (D’Agostino et al., 2020; Kang et al., 2024a; Yao et al., 2018; Figure 1). Given its direct external connection, the lungs are particularly conducive to innate immune modulation by airborne microbes and particulate agents. Thus, the induction and the underlying mechanisms mediating innate immune memory in the respiratory mucosa following local immunological exposure remain a priority of investigation. Within the lung, there are distinct subsets of tissue-resident macrophage populations, including alveolar macrophages (AMs), interstitial macrophages (IMs), and monocyte-derived macrophages (MDMs) (Guilliams and Svedberg, 2021). These subsets differ in their ontogeny, with IMs being mainly yolk sac-derived with slow and continuous input from bone marrow-derived monocytes after birth; whereas, on the contrary, AMs are embryonically derived and self-maintain throughout life (Guilliams and Svedberg, 2021). As the most abundant and important innate immune cells in the lung, AMs are positioned at the airway-environment interface and are continuously exposed to airborne microbes and microbial components, which can imprint the local tissue-resident macrophage niche (Martin et al., 2021). Therefore, their immune phenotype and function is subject to regulation by such environmental exposures (Martin et al., 2021).

Recent studies have demonstrated the induction of tissue-resident memory macrophages following respiratory mucosal exposure to microbial components, vaccines, and infections, and type 2 immunity (Th2), and these macrophages are associated with TII. Respiratory mucosal exposure in mice to microbial components, including lipopolysaccharide (LPS), a Gram-negative bacterial cell wall component, and β-glucan, a fungal cell wall component, has been shown to impact local innate immune responses in the lung and modulate AM function through the induction of innate immune memory and TII (Chakraborty et al., 2023; Kang et al., 2024a; Theobald et al., 2024; Zahalka et al., 2022). LPS-mediated type 1 IFN signaling and metabolic rewiring in AMs play a critical role in the induction of innate immune memory (Zahalka et al., 2022). Notably, while glycolysis appears to be dispensable for the establishment of LPS-induced memory AMs, fatty acid oxidation and glutaminolysis are crucial for its development (Kang et al., 2024a; Zahalka et al., 2022). These cells demonstrate plasticity in surface marker expression, acquiring CD11b and downregulating Siglec F, which returns to baseline upon resolution of LPS-induced acute inflammation (Kang et al., 2024a; Chakraborty et al., 2023). At steady state, these memory AMs are maintained independently of monocyte recruitment and proliferation, akin to naïve AMs (Chakraborty et al., 2023; Kang et al., 2024a; Zahalka et al., 2022). Following subsequent infection or tissue injury, memory AMs remain intact and are sustained without a significant contribution from recruited circulating CCR2⁺ inflammatory monocytes. Additionally, LPS-trained AMs exhibit enhanced efferocytosis, a pro-resolving phenotype, via upregulation of MERTK, a key efferocytosis gatekeeper (Chakraborty et al., 2023). MERTK-expressing AMs also show increased chromatin accessibility to the KLA4 transcription factor, which promotes the resolution of pulmonary fibrosis (Chakraborty et al., 2023). This indicates that LPS-trained AMs exhibit not only a proinflammatory phenotype but also a pro-resolving one, helping to prevent hyperinflammation and restore tissue homeostasis (Chakraborty et al., 2023).

A single low-dose intranasal exposure to β-glucan has been shown to induce low-grade inflammation in the lung, resulting in the development of apolipoprotein E-dependent (ApoE) monocyte-derived AMs that exhibit phenotypic and functional changes characteristic of innate immune memory, such as elevated glycolysis and enhanced phagocytic capacity (Theobald et al., 2024). Local respiratory mucosal β-glucan inoculation recruited ApoE⁺ CD11b⁺ circulating monocytes, which were dependent on CCR2 and M-CSF for maintenance. β-Glucan-trained macrophages exhibited phenotypic and functional adaptations capable of improving the outcomes of pulmonary bacterial infection or fibrosis.

Several live-attenuated human vaccines induce innate immune memory in tissue-resident macrophages and exhibit nonspecific protective effects against heterologous respiratory infections (Sánchez-Ramón et al., 2018). The Bacillus Calmette-Guérin (BCG) vaccine, the only licensed vaccine for tuberculosis (TB), has been shown to modulate the innate arm of the immune system and induce TII in both experimental models and humans (Netea et al., 2016). Although most of the BCG-induced innate immune memory in tissue-resident macrophages has been described following systemic immunological exposure, experimental respiratory mucosal BCG vaccination has also been shown to induce memory macrophages and TII, which are capable of providing protection against heterologous bacterial infection (Mata et al., 2021). Macrophage activation was dependent on IFN-γ produced by CD4⁺ T cells, suggesting that the induction of trained AMs following respiratory mucosal BCG vaccination requires adaptive immunity (Mata et al., 2021). An important effort was made in this study to differentiate BCG bacillus-mediated macrophage activation from the induction of bona fide memory-like macrophages following BCG vaccination. The claim of a memory macrophage phenotype was not made until BCG bacilli were no longer detectable in the lung using the traditional colony-forming unit assay at 7 months post-BCG vaccination, at which time the cellular responses and inflammatory markers in the lung had largely subsided. Some other TII studies, such as the one by Khan et al., 2025, are limited to immunological analysis performed only during the acute phase and not in the resolution phase of immune responses.

Adenovirus (Ad)-vectored vaccination in murine models has also been shown to induce local innate immune memory in tissue-resident macrophages in the lung and TII against homologous or heterologous respiratory bacterial and viral infections (Afkhami et al., 2022; D’Agostino et al., 2020; Yao et al., 2018). Interestingly, memory AM priming, but not the maintenance, was dependent on the help from adaptive T cells, requiring IFN-γ production by CD8⁺ T cells and cell-cell contact (Yao et al., 2018). The development and maintenance of such memory AMs was independent of circulating CCR2⁺ monocytes. Functionally, Ad-vectored vaccine-induced trained AMs and TII provided markedly enhanced protection against pulmonary Streptococcus pneumoniae (S. pneumoniae) (Yao et al., 2018) and SARS-CoV-2 infection (Afkhami et al., 2022). For the latter, TII operated via inducing viral disease tolerance but not by altering viral clearance. This contrasts with the training phenotype induced by a single low-dose respiratory LPS exposure, which generated trained AMs and protected against S. pneumoniae but not SARS-CoV-2 infection (Kang et al., 2024a). These observations highlight the complexity and differential outcomes of lung-resident memory macrophages and TII, depending on the nature of training stimuli.

Furthermore, the intranasal polymicrobial MV130 vaccine induced airway memory macrophages and TII against heterologous respiratory infections in mice (Brandi et al., 2022; Del Fresno et al., 2021). The composition of the resulting memory airway macrophage population was also independent of circulating monocytes. The development of memory macrophages in the lung was dependent on the mTOR pathway (Brandi et al., 2022). However, one caveat in this study is that repetitive intranasal doses of MV130 may have induced a sustained immunostimulatory/activating effect on tissue-resident macrophages. Nonetheless, the above findings together support the immunological benefits of respiratory mucosal-delivered vaccines in inducing both tissue-resident memory innate and adaptive immune cell types for clinical application. Indeed, the persisting changes have been observed in human AMs following inhaled aerosol Ad-vectored vaccination against TB (Jeyanathan et al., 2022a) or COVID-19 (Jeyanathan et al., 2025) or ex vivo exposure to IFN-γ (Cox et al., 2024).

In addition to attenuated vaccines and microbial components, common respiratory pathogens, including influenza A virus (IAV), SARS-CoV-2, and S. pneumoniae that typically cause acute infections, are able to induce airway memory macrophages and TII in experimental models (Aegerter et al., 2020; Guillon et al., 2020; Lercher et al., 2024; Wang et al., 2023). Such memory AMs were of monocytic origin, and their generation was dependent on NK cell-derived IFN-γ. Recruitment of circulating monocytes to the lung following acute IAV infection replenished the depleted AM pool and acquired the phenotype of tissue-resident AMs over time (Aegerter et al., 2020). Recovery from past SARS-CoV-2 infection induced innate immune memory AMs via functional changes associated with innate immune memory and TII against secondary IAV infection (Lercher et al., 2024). Following mild SARS-CoV-2 infection, the imprinted airway-resident macrophage population was maintained independently of circulating monocytes, as there was limited contribution of MDMs to the resident AM pool. Recovered imprinted airway-resident macrophages were enriched in genes associated with antiviral immunity and IFN responses, and type 1 IFN signaling was involved in the development of memory AMs (Lercher et al., 2024). This demonstrates how a history of viral infection can have a significant effect on the subsequent development of disease. Similarly, recovery from pneumococcal pneumonia reprograms the AM pool, and such experienced AMs exhibit characteristics associated with innate immune memory and TII (Arafa et al., 2022). Induction of memory AMs was dependent at least in part on IFN-γ, which was produced by a variety of cells, including CD4⁺ T cells. Following pneumonia, the resident embryonic-derived AM population was replaced by MDMs, which displayed similar phenotypic characteristics as resident AMs. Thus, environmental signals and tissue niche, rather than ontogeny, dictate macrophage phenotype. These findings suggest that exposure to different common respiratory viral and bacterial pathogens can alter the local innate immune landscape and makeup of the tissue-resident macrophage population in the lung depending on the pathogen, severity, and duration of infection.

 While respiratory pathogens have been well characterized to induce innate immune memory and TII in tissue-resident macrophages, noninfectious inflammatory diseases, such as chronic inflammatory diseases and cancer, can also lead to alterations in innate immune cells in the lung (Niec et al., 2021). While the induction and mechanisms of innate immune memory are relatively well understood following local exposure to microbial components, vaccines, and infections, the induction, mechanistic underpinnings, and consequences of innate immune memory and TII induced in Th2 conditions, including allergy and asthma, are only beginning to emerge (Hartung and Esser-von Bieren, 2022). The emerging evidence suggests that house dust mite (HDM)-allergic mice and patients develop M2-like inflammatory memory macrophages in the lung and bone marrow (Lechner et al., 2022). However, the longevity of such HDM-trained lung macrophages and whether they may translate to enhanced innate immune protection remains to be investigated. It is unclear which type of lung-resident macrophages and TII may result from sequential respiratory exposure to an infectious agent/vaccine and an environmental-borne agent such as HDM in the same host. Repeated respiratory immunological exposure is a clinically relevant setting in human lungs where the preexisting TII is expected to be impacted by the effect of a secondary TII-inducing agent and vice versa, likely settling in a re-established and complex innate immune memory environment.

Clearly, depending on the nature of the respiratory mucosal stimuli, the composition of the resulting airway memory macrophage population may differ. While AMs trained by vaccines or microbial components causing limited inflammation are primarily of tissue-residential/embryonic origin, those resulting from more potent stimulation caused by an infection or severe inflammatory response may originate largely from recruited monocytes (Figure 1). For instance, exposure to certain mucosal stimuli, such as herpes simplex or influenza virus, largely replaces resident AMs with recruited MDMs, while a higher proportion of bona fide resident AMs persist following mucosal exposure to Ad-vectored vaccine or a TLR agonist such as LPS (Kang et al., 2024a; Yao et al., 2018). Indeed, it has been found that airway-resident AMs can temporarily downregulate and re-gain Siglec-F expression accompanied by acquisition and downregulation of CD11b following a single low-dose respiratory LPS exposure (Kang et al., 2024a). It is, however, noteworthy that in some instances of acute lung infection or inflammation, there could be a temporary reduction in the tissue-resident AM population known as the ‘macrophage disappearance reaction’, which reflects the ability of AMs to adapt a different immune phenotype during acute infection and reset their phenotype back to resident AMs in the resolution phase (Aegerter et al., 2022; Janssen et al., 2011; Kang et al., 2024a). Such temporary reduction in tissue-resident AMs as defined by cell surface immunostaining should not be mistaken for bona fide depletion of AMs and its subsequent replenishment by MDMs without other evidence than surface immunostaining.

Until recently, prevailing evidence suggested a paradigm of compartmentalization in the development of resting-state innate immune memory, shaped by recent history of immunological imprinting. According to this view, trained hematopoietic progenitors and circulating monocytes are associated with systemic or parenteral exposure to biotic/abiotic factors or vaccines, whereas the innate immune memory in mucosal-resident macrophages at barrier sites is attributed to local biotic/abiotic exposure or vaccination. However, recent findings challenge this notion, revealing that remote exposure to immune stimuli can have far-reaching training effects on innate cells at distant barrier tissue sites, such as the peritoneal cavity and lung (Jeyanathan et al., 2022b). This newly emerged type of immunological action can be referred to as distally imparted local training (Figure 1).

It has been well documented that intravenous BCG (ivBCG) vaccination reprograms hematopoietic stem cells (HSCs) in the bone marrow toward myelopoiesis, fostering innate immune memory in peripheral myeloid cells (Kaufmann et al., 2018). Until recently, it was unclear whether parenteral or subcutaneous BCG (scBCG) vaccination, a non-mucosal route of microbial exposure, could impact lung tissue-resident macrophages (Jeyanathan et al., 2022b). In mice immunized with a low dose of scBCG, AMs display key features of innate immune memory, including increased MHCII expression, enhanced phagocytic capacity, increased glycolysis, and oxidative phosphorylation (Jeyanathan et al., 2022b). Induction of trained AMs occurs in the absence of BCG dissemination to the lung. These trained AMs provide enhanced early protection against Mycobacterium tuberculosis (Mtb) – the intended target pathogen of the BCG vaccine – preceding adaptive T cell immunity in the lungs, and they also offer protection against heterologous S. pneumoniae infection, independent of centrally trained circulating monocytes (Jeyanathan et al., 2022b; Kang et al., 2023). These experimental findings are supported by epidemiological evidence in children and adults showing nonspecific protection by cutaneous BCG vaccination against respiratory infections and mortality (Giamarellos-Bourboulis et al., 2020; Stensballe et al., 2005). Transcriptional reprogramming in these AMs results in increased expression of a defense-ready gene signature, including interferon-associated responses, as well as increased expression of cell cycle markers indicative of proliferation (Jeyanathan et al., 2022b; Mai et al., 2024). Interestingly, a contained intradermal infection of Mycobacterium tuberculosis (CMTB) in mice also enhances protection against heterologous Listeria monocytogenes infection and lung metastasis of B16 melanoma cells, which is associated with reprogramming of tissue-resident lung macrophages (Nemeth et al., 2020). Like after scBCG immunization, AM remodeling in these mice occurs without Mtb dissemination to the lungs. However, ongoing interactions between the immune system and live Mtb are essential for maintaining TII, as antibiotic treatment following Mtb exposure diminishes protective immunity against secondary infections. Supporting this, inactivated BCG fails to induce innate immune memory in AMs (Jeyanathan et al., 2022b). Remarkably, AM reprogramming persists long after parenteral exposure to either BCG or Mtb. This innate immune memory in AMs develops locally within the self-renewing AM population, with a minimal contribution from circulating MDMs, highlighting the role of local signals rather than the involvement of myelopoiesis in the bone marrow. Of note, gross cellularity in the airways of either scBCG or CMTB mice remains unaffected after exposure (Jeyanathan et al., 2022a; Mai et al., 2024).

In contrast to findings from experimental models, AMs isolated from the sputum of BCG-vaccinated individuals display reduced levels of activation markers, such as CD11b and HLA-DR post-vaccination (Koeken et al., 2020). Moreover, these sputum-derived AMs exhibit a lack of response to microbial products, possibly due to a heightened activated state upon isolation. This observation contradicts the known responsiveness of AMs obtained via bronchoalveolar lavage, which typically respond to ex vivo stimulation (Mwandumba et al., 2007). This raises the question of whether this hyperresponsiveness is an inherent feature of sputum-derived AMs, which largely reside in the upper respiratory tract, or if they differ fundamentally from lower respiratory tract AMs in BCG-vaccinated individuals. It is important to note that the immune profile at baseline affects how well innate immune memory develops after BCG vaccination. The vaccine enhances innate immune memory in those with a dormant baseline immune state, rather than providing a broad immune boost across all individuals (Moorlag et al., 2024). Additionally, in humans, the degree of training in peripheral myeloid cells is influenced by the BCG strain (Xu et al., 2024) and even the time of day when BCG is administered (de Bree et al., 2020). Future studies should investigate how these factors affect the induction of innate immune memory in lung-resident macrophages following BCG vaccination. Further understanding of the relationship of cutaneous BCG vaccination to lung-resident macrophage training and its heterogeneity will shed light on the innate immune mechanisms underlying TB resistance observed in a proportion of Mtb-exposed humans (Koeken et al., 2019).

Unlike the IFN-γ-dependent induction of innate immune memory in HSCs in the bone marrow following ivBCG vaccination (Kaufmann et al., 2018), the induction of innate immune memory in AMs by scBCG occurs independently of IFN-γ in murine models (Jeyanathan et al., 2022b). Instead, innate immune memory in AMs after scBCG is linked to gut microbiota dysbiosis and elevated levels of short-chain fatty acids (SCFA), carnitine, and butyrate in the intestine, circulation, and lung tissue (Jeyanathan et al., 2022b). Microbiota transplantation or SCFA supplementation via drinking water in naïve mice replicates these effects, indicating a causal link between BCG-induced gut microbiota changes and the development of memory AMs. This points to a gut-lung axis in the induction of innate immune memory in AMs (Roquilly and Villadangos, 2022). In this regard, intestinal colonization by segmented filamentous bacteria (SFB) leads to reprogramming of AMs, enhancing their ability to control respiratory viruses and reduce disease severity (Ngo et al., 2024). However, the specific signal from SFB colonization that drives AM reprogramming remains unclear. The aforementioned findings highlight the role of fatty acids and their metabolic products in reprogramming lung-resident macrophages. Lipid mediators – bioactive signaling molecules generated by the oxidation of polyunsaturated fatty acids like arachidonic acid (AA) – serve as key signaling agents in establishing innate immune memory in monocytes following scBCG vaccination in humans (Ferreira et al., 2023). Monocytes trained in vitro with BCG exhibit elevated levels of metabolic products from two major enzymatic pathways: cyclooxygenase and lipoxygenase, which metabolize AA into eicosanoids. To this end, AMs are a significant source of bioactive lipids that act as key sensors in regulating pulmonary immunity during viral infection (Pernet et al., 2024). However, it remains to be determined whether systemic exposure to immune stimuli induces production of lipid mediators by AMs and plays a role in memory formation and maintenance. Understanding the interaction between lipid mediators and pulmonary macrophages could have important implications for developing therapeutic strategies against respiratory infections.

Although numerous studies have established that parenteral exposure to defined microbial products trains bone marrow and circulating myeloid cells, its influence on tissue-resident macrophages at distal barrier sites remains relatively underexplored. Recent evidence demonstrates that parenteral β-glucan exposure in mice significantly impacts lung-resident macrophages by enhancing their efferocytic capacity and providing critical survival signals to epithelial cells, thereby increasing resilience to bleomycin-induced tissue injury (Kang et al., 2024b). While the precise role of monocyte myelopoiesis in contributing to the lung tissue-resident memory macrophage pool remains unclear, β-glucan treatment promotes the recruitment of apoptotic neutrophils to the lung, correlating with histone modifications in AMs. These trained AMs exhibit upregulated expression of Il4ra and Il13ra gene transcripts and produce elevated levels of the lipid mediator resolvin D1 (RvD1). Notably, alveolar epithelial cells cultured in conditioned media from these trained AMs display enhanced expression of SIRT1, which is associated with reduced epithelial apoptosis (Kang et al., 2024b). These findings suggest that parenteral exposure to microbial products can also exert significant effects on tissue-resident macrophages, highlighting a novel mechanism for enhancing epithelial cell protection in barrier tissues.

Studies have further shown that acute tissue injury can induce innate immunity in distal barrier tissue sites of mice. AMs exhibit increased proliferation, heightened expression of epidermal growth factor receptor (EGFR), and increased epidermal growth factors in the lung following myocardial infarction (MI) (Hoyer et al., 2019). The AM population remains stable post-MI, with initial priming occurring independent of circulating monocytes, but rather through IFN-γ produced by lung-recruited NK cells. Importantly, AMs show enhanced phagocytic activity and provide enhanced pathogen clearance during subsequent respiratory bacterial infection, such as those caused by S. pneumoniae, while they contribute to inflammatory lung injury due to increased EGFR signaling (Hoyer et al., 2019). Interestingly, the pathogen clearance benefits seen after MI are not observed following stroke or sepsis, despite similar alterations in AMs. Although whether such distal injury-induced changes in AMs remains unclear, this study raises the possibility that lung-resident macrophages may undergo changes in response to a wide array of immunological events occurring at other tissue sites.

Current evidence suggests that monocytes play a relatively minor role in the development and maintenance of innate immune memory in lung tissue-resident macrophages, particularly AMs, following remote exposure to immune stimuli. This contrasts with observations following local exposure, where the degree of inflammation can lead to various outcomes, from no replacement to partial or complete replacement of lung tissue-resident macrophages by circulating monocytes (Figure 1). In murine studies, AMs are seeded during embryonic development and can self-replenish independent of circulating monocytes throughout adulthood (Guilliams and Svedberg, 2021). However, less is known regarding the ontogeny of airway macrophages in the human lung. A recent study demonstrated that, in lung transplant patients, the majority of airway macrophages were replaced by circulating monocytes, which differentiated into mature AMs (Byrne et al., 2020). This suggests that the ontogeny of human AM population may be more dynamic and less stable than murine counterparts and emphasizes the importance of delineating the origin of AMs in human and murine lungs (Byrne et al., 2020). Furthermore, this raises the question as to how applicable murine models are to humans, and the data should be interpreted with caution. Since the majority of murine models used are kept in SPF conditions and are inbred, they do not accurately recapitulate the respiratory mucosal environment in humans. Thus, a better model to aid in the translation of murine models to humans would be to adopt a mouse model that closely resembles humans, including the use of pet store or deer mice (Hamilton et al., 2020; Kitching and Ooi, 2016). There also remains a gap in our understanding of how both local and remote exposure to immune stimuli affects other lung tissue-resident macrophage populations besides AMs, including IMs. However, the distinct microenvironment where AMs reside, which are isolated from circulation during homeostasis (Hashimoto et al., 2013), unlike IMs, may explain why the memory AM population remains intact without significant monocyte contribution following either a local or remote immunological event.

The field of remote immune modulation of lung-resident macrophages represents a promising frontier for both basic and clinical research. Understanding how innate immune memory forms in barrier tissues, in the context of interorgan immune communication via host- and natural microbiota-derived signals, has the potential to revolutionize vaccine strategies and therapies for lung diseases and enhance vaccine strategies against respiratory infections. Moving forward, research must delve into the specific molecular mechanisms involved and carefully evaluate the risks of respiratory mucosal and systemic immune approaches, especially in the context of autoimmune diseases.

In the past decade, systemic – and more recently, local – immunological exposure to various microbial components, vaccines, and infections has been shown to alter the innate immune cell compartment, specifically within the tissue-resident macrophage population at mucosal sites (Netea et al., 2016; Xing et al., 2020). It is known that such immune or inflammatory memory within the innate immune cell compartment can result in a strengthened immune response leading to enhanced innate immune protection against either a homologous or heterologous pathogen/entity (Table 1). As described in the Introduction, the altered innate immune protective outcome resulting from innate immune memory is referred to as TII. Since locally or centrally induced TII is capable of heightened innate immune responses and protection against a broad range of pathogens and entities in the lung, its protective mechanisms may vary widely and are thus worthy of separate considerations.

Beyond the lung, tissue-resident memory macrophages and TII are also induced at other barrier tissues, such as the skin, gut, and peritoneal cavity. This induction enhances innate immune responses, allowing these tissues to mount more rapid and effective TII against subsequent unrelated pathogens.

Compared to our knowledge in innate immune memory and TII associated with innate immune cells and their progenitors, limited information is available for nonimmune innate tissue structural cells. However, recent evidence indicates the acquisition of long-lasting innate inflammatory memory and TII in nonimmune or structural cells in the lung (Hamada et al., 2018). Furthermore, inflammatory memory has been shown in stem cells within other barrier tissue sites, such as the skin (Cheng et al., 2023). Like trained innate immune cells, such trained nonimmune cells are also capable of TII against subsequent heterologous pathogen exposure.

Indeed, in addition to tissue-resident macrophages in the lung, bronchial epithelial cells (BECs) participate in innate host defense and are among the first cells to encounter inhaled respiratory pathogens (Bigot et al., 2025). Recently, flagellin exposure in mice has been shown to modify the inflammatory phenotype of BECs following secondary exposure to unrelated immune stimuli via sustained epigenetic modifications (Bigot et al., 2025; Bigot et al., 2019). Pre-exposure of BECs with Pseudomonas aeruginosa flagellin in vitro induced histone modifications altering gene expression leading to modulation of the inflammatory response to subsequent heterologous exposure to immune stimuli. Such memory BECs produced elevated levels of cytokines IL-8 and IL-6 following secondary exposure to a live fungal pathogen; in contrast, they exhibited a decreased inflammatory response against subsequent LPS stimulation (Bigot et al., 2019).

On the other hand, recent advances in the field showed enhanced wound healing after the skin of mice was exposed to imiquimod, a topical immune response modifier, suggesting skin epithelial stem cells can retain inflammatory memory in response to tissue damage (Cheng et al., 2023; Naik et al., 2017). In a model of skin inflammation, epithelial stem cells demonstrated inflammatory memory associated with long-lasting chromatin modifications acquired following tissue damage (Naik et al., 2017). Such inflammatory-induced memory skin epithelial stem cells display a heightened response to subsequent stressors associated with enhanced wound healing. However, the mechanisms underlying such inflammation-induced rewiring of skin epithelial stem cells require further investigation. Inflammation-experienced memory skin epithelial stem cells may underlie recurrent skin inflammation displayed in autoimmune skin disorders and may have implications for future therapeutic strategies.

Besides lung and skin epithelial cells, the limited but emerging evidence also suggests the epithelial cells at other barrier tissues, such as the intestine, to acquire inflammatory memory and TII (Chen et al., 2024). Specifically, this was demonstrated in intestinal tuft cells primarily mediated by IL-25 in a murine enteroviral infection model. While the data obtained largely from in vitro models also suggest the induction of inflammatory memory in other structural cells, such as smooth muscle cells and fibroblasts, further in vivo investigation is required.

Harnessing TII offers a promising avenue for development of new intervention strategies against the current and emerging infectious threats where pathogen-specific vaccines may not yet be available. Compared to conventional vaccines that are designed to primarily induce target pathogen-specific adaptive immunity and protection (Figure 2), nontarget-specific TII-based vaccine or agent is designed to train innate immune cells and offer broad nonspecific TII against a variety of pathogens. In this case, a manufactured, scaled-up vaccine with known TII-inducing effects, developed for an unrelated pathogen, could be quickly deployed as a ‘bridge vaccine’ for controlling new emerging infectious threats. Similarly, the biologic agents, particularly PAMPs (pathogen-associated molecular patterns) such as β-glucan, are able to induce centrally induced or tissue-resident TII and thus can also be employed for the same purpose. These could serve as a critical measure to bridge the gap before the target-specific vaccine becomes available (Figure 2).

Figure 2

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Conversely, we should also harness our knowledge in TII to continue to develop next-generation vaccine strategies that are both target-specific and TII-based. Such vaccines are expected to induce robust and persisting innate and adaptive immune memory responses, thus offering both nonspecific and specific immune protection (Figure 2). During the COVID-19 pandemic, the nonspecific protective effects of the BCG vaccine were speculated to extend heterologous protection against SARS-CoV-2. However, clinical trials examining whether BCG-induced TII protects against COVID-19 showed contradictory results (Noble et al., 2023). Some trials showed a significant reduction in the development of COVID-19, whereas others showed BCG vaccination to have no effect on the development of COVID-19 (Pittet et al., 2023; Tsilika et al., 2022). Understanding the best ways to exploit off-target effects of the BCG vaccine will be of help to designing next-generation vaccination strategies. Rational design of next-generation vaccine strategies involves the prudent consideration of the route of vaccine delivery, choice of viral vector, and multi-antigenicity. Both preclinical and clinical evidence suggests the deep respiratory mucosal delivery of chimpanzee Ad-vectored multi-antigenic vaccine to effectively elicit tripartite mucosal immunity consisting of TII, mucosal antibody responses, and tissue-resident memory T cell immunity (Afkhami et al., 2022; Jeyanathan et al., 2025). This type of vaccine-induced mucosal immunity is expected to offer the most effective protection against the intended target pathogen and a wide range of unrelated respiratory pathogens.

The emerging knowledge also suggests that different human vaccines and immunization strategies have differential effects on induction of TII (Benn et al., 2023). Specifically, the live and non-live vaccines exhibit differential outcomes of heterologous protection. Live vaccines demonstrate beneficial nonspecific effects and improve overall health and mortality, whereas non-live vaccines have negative nonspecific effects and increase overall all-cause mortality largely in females (Benn et al., 2020). Additional investigation is required to understand such discrepancies between males and females. Furthermore, the current childhood vaccine programs, especially in developing countries, may consider favoring the use of live vaccines over non-live vaccines as the former are more effective in inducing TII. There is also the evidence that the formula of the most recently administered vaccine dictates the presence of residual TII-inducing effects, and that combined delivery of live and non-live vaccines may introduce variable or confounding heterologous protective benefits (Benn et al., 2020).

The concept of innate immune memory and TII has advanced significantly over the past decade or so, revealing complex interactions between tissue-resident macrophages and circulating innate immune cells, in response to various immunological exposure. While TII offers promise for enhancing innate immune protection against unrelated pathogens, lung injury, and tumors, it could constitute a mechanism underlying maladaptive inflammation or tissue damage. Overall, it is important to note that induction of innate immune memory and TII following either systemic or local exposure is not created in the same way in terms of innate immune functional outcomes and mechanisms. The differential outcomes of TII in various infection contexts, particularly regarding disease tolerance, highlight the necessity for precise strategies in vaccine and immunotherapy development. As research continues, the coming years are poised to yield deeper insights into the mechanisms underlying TII, potentially revolutionizing clinical approaches to immune modulation and disease prevention.

Moving forward, further investigation is needed to address the longevity of trained tissue-resident macrophages and TII, as currently many in vivo studies were performed during acute phases of the immunological response. We still understand relatively little about the interaction of memory macrophages with tissue structural cells and other immune cells at barrier tissues. We should also make an effort to reach into under-investigated barrier tissue sites, particularly the gut and urogenital tract. More research is required to understand the nature of innate immune environment following multiple immunological exposure. The impact of systemic immunological stimuli on local innate memory and TII at barrier tissue sites needs to be further explored. Key knowledge gaps still remain, and all these questions remain to be addressed at both ends of the life spectrum. Furthermore, we need to continue to study the commonalities and differences and the potential intersection between trained tissue-resident macrophage subsets generated following local Th1 and Th2 immunological exposure.

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Author details

1. Alisha Kang

   McMaster Immunology Research Centre, Department of Medicine, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Canada

   Contribution

   Data curation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

2. Michael D'Agostino

   McMaster Immunology Research Centre, Department of Medicine, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Canada

   Contribution

   Data curation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Sam Afkhami

   McMaster Immunology Research Centre, Department of Medicine, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Canada

   Contribution

   Data curation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

4. Mangalakumari Jeyanathan

   McMaster Immunology Research Centre, Department of Medicine, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Canada

   Contribution

   Conceptualization, Data curation, Writing – original draft, Writing – review and editing

   For correspondence

   jeyanat@mcmaster.ca

   Competing interests

   No competing interests declared

5. Zhou Xing

   McMaster Immunology Research Centre, Department of Medicine, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Canada

   Contribution

   Conceptualization, Data curation, Writing – original draft, Writing – review and editing

   For correspondence

   xingz@mcmaster.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7856-0663

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