pulmonary injury :: Article CreatorTargeting TREM2 On Lung Immune Cells Offers Promising New Approach To Treat Pulmonary Fibrosis
Lung macrophages, a type of white blood cell vital for immune defense, play a crucial role in conditions such as idiopathic pulmonary fibrosis (IPF). There are two main varieties of these cells in the lungs: tissue-resident macrophages, which are present from birth and help maintain lung health, and monocyte-derived macrophages (Mo-AMs), which are recruited temporarily to the lungs in response to injury or infection.
Recent research has identified Mo-AMs as significant contributors to the development and progression of lung fibrosis. Despite this discovery, the underlying mechanisms that drive their fibrotic activity and enable their survival in the lung environment remain poorly understood, leaving clinicians without effective targeted treatments for the disease.
Researchers at the University of Alabama at Birmingham (UAB), led by Gang Liu, M.D., Ph.D., and Huachun Cui, Ph.D., looked to learn more.
In a study published in Nature Communications earlier this year, the researchers concentrated specifically on the Mo-AM subgroup and uncovered a crucial mechanism by which these cells contribute to lung fibrosis.
The UAB researchers demonstrated that TREM2 — short for triggering receptors expressed on myeloid cells 2 — is primarily found on monocyte-derived alveolar macrophages in mice with bleomycin-induced lung fibrosis. Additionally, they observed that TREM2 levels were notably higher on lung macrophages from patients suffering from idiopathic pulmonary fibrosis.
The findings indicate that TREM2, a receptor highly expressed on Mo-AMs and significantly upregulated in macrophages from IPF patients, plays a central role in driving this disease process, leading to the authors noting TREM2 is a promising target for developing therapies aimed at counteracting the fibrotic activity of this important cell population in lung fibrosis.
"We have found an important mechanism by which these Mo-AM cells promote lung fibrogenesis," Liu said in a new release issued by the university. "Our data suggest that TREM2, which is highly expressed in Mo-AMs and markedly induced in idiopathic pulmonary fibrosis macrophages, is a key mediator in this pathology and a valuable target for developing strategies to neutralize the pro-fibrotic effect of this pathologically significant group of cells in lung fibrosis."
What's more, the researchers demonstrated that a TREM2-blocking antibody eliminated the protective effects of soluble TREM2 on macrophages and reduced lung fibrosis. This indicates that inhibiting TREM2's interaction with its ligands could be an effective therapeutic approach for treating lung fibrosis in the future.
"We found that Mo-AM TREM2 is a key mediator of the pro-fibrotic activity of these cells in lung fibrosis," the authors said. "Our findings improve the mechanistic understanding of the crucial role of Mo-AMs in the pathogenesis of this disease."
They noted in their Nature Communications that a recently published report showed that mice deficient in Mo-AM TREM2 were protected from bleomycin-induced lung fibrosis. "Although the underlying mechanism identified in that study differs from what is demonstrated here, both studies suggest that Mo-AM TREM2 represents a promising therapeutic target for lung fibrosis," they wrote.
One wrinkle in the MoAM TREM-2 narrative is that monocyte-derived macrophage TREM2 has been shown to play a beneficial role in other contexts of organ fibrosis, particularly in metabolic liver diseases, according to Liu, Cui and their co-authors.
"The apparently divergent roles of monocyte-derived macrophage TREM2, and even monocyte-derived macrophages themselves, in influencing the progression and resolution of tissue fibrosis across different organs underscore the evolving understanding that macrophage phenotype, function, and adaptation are shaped by both their ontogeny and the local environment," they wrote in Nature Communications.
Acute Lung Injury: The Double-edged Nature Of Trained Immunity
The concept of trained immunity has transformed our understanding of how the innate immune system responds to stimuli. For many years, the responses of innate immune cells – such as monocytes, macrophages, natural killer cells and neutrophils – were seen as short-lived and non-specific. However, we know now that these immune cells can adapt their responses after being exposed to a stimulus for the first time. This initial encounter trains these cells to respond more vigorously to subsequent challenges, which typically leads to increased resistance to various infections. This memory-like state is typically triggered by microbial components like β-glucan, the BCG vaccine, and certain endogenous signals (Netea et al., 2020). The training that follows these exposures results in long-term changes in transcription, chromatin structure and cellular metabolism in the immune cells. However, while trained immunity is often protective, it can also carry costs.
Deep in the lungs, for example, cells called alveolar macrophages are constantly bombarded with inhaled chemicals, pathogens and particulates, and these cells play a crucial role in balancing immune responses while keeping inflammation at bay. However, molecules known as lipopolysaccharides, found in the membranes of certain bacteria, can lead to excessive inflammation, resulting in acute lung injury. The relationship between trained immunity and inflammation has so far remained unclear.
Now, in eLife, Maziar Divangahi of McGill University and colleagues – including Renaud Prével as first author – report more insights into the double-edged nature of trained immunity in the lungs (Prével et al., 2024). The researchers investigated whether β-glucan can induce trained immunity in alveolar macrophages in mice, and how this affects acute lung injury.
Mice were injected with β-glucan and, seven days later, were treated with bacterial lipopolysaccharide or an immunostimulant called poly(I:C) to simulate viral infections. Mice that received bacterial lipopolysaccharide exhibited an increased number of neutrophils in the lungs. Furthermore, they developed elevated levels of several inflammatory chemical messengers, such as TNF-α, IL-6 and CXCL1, and displayed signs of acute lung injury (Figure 1). Mice treated with the immunostimulant also demonstrated a rise in neutrophils and chemical messengers, apart from TNF-α, which remained unchanged.
Trained immunity and acute lung injury.
Injecting mice with β-glucan (Signal 1) resulted in trained immunity for alveolar macrophages (left panel). This trained immunity depended on neutrophils and type II interferon signalling (IFNγ). The macrophages remained in their trained state when transferred into mice that lacked immune cells (middle panel). Exposure to a secondary challenge (Signal 2) – such as a bacterial stimulus (LPS) or a viral stimulus (poly(I:C)) – later re-engaged the trained macrophages and induced a strong inflammatory response. This response includes neutrophil influx and increased production of several inflammatory chemical messengers (IL-6, CXCL1 and TNF- α), which led to acute lung injury (right panel). LPS: lipopolysaccharides; poly(I:C): polyinosinic:polycytidylic acid; AM: alveolar macrophage; IL-6: interleukin 6; CXCL1: chemokine (C-X-C motif) ligand 1; TNF-α: tumor necrosis factor alpha. This figure was created with BioRender.Com.
The work of Prével et al. Is consistent with studies that have reported that β-glucan aggravates disease in models of periodontitis and arthritis (Haacke et al., 2025). However, this contrasts with previous work, which showed that training with β-glucan can reduce lung fibrosis caused by exposure to the chemotherapy drug, bleomycin (Kang et al., 2024). These conflicting findings emphasize the need to understand the contexts in which trained immunity may backfire.
Prével et al. – who are based at McGill University and institutes in Morocco and France – confirmed that alveolar macrophages are key mediators of the exaggerated immune response. Following β-glucan exposure, the number of immune cells in the lungs remained unchanged; however, the macrophages underwent metabolic and transcriptional reprogramming, which led to an increase in the production of inflammatory cytokines. This suggests that functional changes in the macrophages, rather than an increase in cell number, leads to stronger inflammation. Furthermore, transplanting trained alveolar macrophages into mice lacking these cells, followed by administration of lipopolysaccharide, initiated a heightened inflammatory response. This demonstrated that the phenotype is intrinsic to alveolar macrophages and independent of circulating monocytes.
Prével et al. Also found that β-glucan training required type II interferon signaling but not type I. This contrasts with previous work showing a key role for the latter in lipopolysaccharide-trained alveolar macrophages exposed to pneumococcal bacteria (Zahalka et al., 2022). Indeed, type II interferon signaling has also been implicated in training macrophages in response to bacterial, fungal and viral infections (Leopold Wager et al., 2018; Tran et al., 2024; Wang et al., 2023; Arafa et al., 2022).
Based on these results, Prével et al. Go on to propose a framework in which the nature of the initial training signal (signal 1) and the nature of the secondary challenge (signal 2) determine the immunological outcome of trained immunity (Figure 1). This framework implies that trained immunity is not defined solely by the training signal, but also by the context in which the cells are re-engaged.
Other variables may also influence the outcomes of trained immunity, including differences in laboratory readouts (e.G., cytokines, tissue damage, microbial clearance) and routes of administration. For example, intravenous but not subcutaneous administration of the BCG vaccine enhanced antiviral responses of alveolar macrophages (Tran et al., 2024).
Perhaps most importantly, the source and environment of the responding immune cells matter greatly. Much research has focused on blood-derived monocytes and their progenitors, including hematopoietic stem cells (Moorlag et al., 2020; Kaufmann et al., 2018; Netea et al., 2020). However, resident macrophages in tissues like the lung are increasingly recognized as key players in local trained immunity (Tran et al., 2024; Zahalka et al., 2022; Chakraborty et al., 2023; Prével et al., 2024). Moreover, neighboring immune cells can also shape trained immunity, as shown by the fact that neutrophils are required for the training of alveolar macrophages in the current study.
The study of Prével et al. Is particularly compelling because, in addition to being found in the cell walls of bacteria, β-glucan is also a ubiquitous component of fungal cell walls, many of which reside within our microbiota. This raises the possibility that alveolar macrophages are constantly trained by our unique environments, lifestyles and even age.
The developmental history of alveolar macrophages adds another layer of complexity. Resident alveolar macrophages arise from fetal monocytes and self-renew, but during infection or injury, they can be replaced by monocyte-derived alveolar macrophages. These recruited cells are often more inflammatory, which helps to fight pathogens but also carries a higher risk of tissue damage. Future studies to assess how β-glucan training affects the development of the lung macrophage population will be of interest as well as the durability and molecular basis of the trained state.
Ultimately, the work of Prével et al. Offers a nuanced view of trained immunity in an organ where immune restraint is often more important than immune reactivity. Understanding how trained immunity is shaped by training and cellular origin, signaling molecules, and the environment will be essential. As we continue to explore how innate immune memory is generated and maintained, one thing is clear: context is everything.
Alcohol-related Lung Disease: Symptoms And More - Medical News Today
Alcohol-related lung disease (ARLD) is an umbrella term for lung problems that relate to excessive alcohol consumption. This damage may result from various lung conditions, such as viral infections, pneumonia, and acute lung injury.
ARLD is a potential complication of alcohol use disorder (AUD). Chronic use of alcohol causes inflammation and harms the immune system. Eventually, this can lead to lung diseases and infections.
ARLD can refer to any lung problems that chronic alcohol consumption has influenced, including pneumonia, tuberculosis (TB), and acute respiratory distress syndrome (ARDS).
Long-term heavy drinking causes inflammation and eventually harms the immune system. Over time, this can start to affect the lungs, making the body more vulnerable to lung infections and damage.
This is known as ARLD, which may present as several lung problems, such as pneumonia or TB. It can result from AUD.
As AUD can impair a person's immunity, it may increase the risk of the following infectious lung diseases:
The symptoms of ARLD depend on the type of lung disease a person develops. Some examples are below.
Pneumonia signs and symptoms
Pneumonia is the medical term for infection and inflammation of the tiny air sacs or "alveoli" within the lungs.
A person who misuses alcohol over a long period may be more vulnerable to pneumonia.
TB signs and symptoms
TB is an airborne bacterial infection that primarily affects the lungs. A TB infection may be more severe in those with a history of alcohol misuse.
According to the ALA, TB may cause the following symptoms:
a cough lasting more than 3 weeks appetite loss weight loss fever, chills, and night sweats
RSV
RSV is a common respiratory infection that typically causes mild, cold-like symptoms.
However, people with weakened immune systems, such as those who have misused alcohol for a long time, are at increased risk of developing severe and potentially life threatening symptoms.
According to the ALA, a barking or wheezing cough is often one of the first signs that RSV is developing into a serious illness.
Additionally, chronic use of alcohol makes people more vulnerable to other viral infections, not just RSV.
ARDS
ARDS is the medical term for acute lung injury resulting from infection or trauma.
People with a history of alcohol misuse may be more vulnerable to ARDS and may have more severe symptoms.
ARDS is a life threatening condition. Symptoms of the condition may include the following:
If a person begins to worry about their drinking and its effects on their physical health, they can contact a doctor.
A doctor can refer them to an AUD specialist and recommend counseling. They can also start treatment for any conditions present.
People may find it difficult to seek help for AUD, but several services and organizations can provide support.
If someone wishes to seek help or learn more about AUD, some helpful organizations include:
People may wish to reach out to family and friends, as any support is helpful when tackling AUD.
ARLD describes lung problems that result from excessive alcohol consumption. It is a possible complication of AUD.
Excessive alcohol consumption can weaken a person's immune system, increasing their susceptibility to lung conditions, such as pneumonia, respiratory syncytial virus (RSV), and acute respiratory distress syndrome.
Excessive alcohol consumption can also worsen asthma and increase the risk of choking and aspiration pneumonia.
Those who have concerns about their lung health or alcohol consumption can consult their doctor for further advice and guidance.
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