Exploring the versatile roles of tissue macrophages beyond immune defense

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A recent study published in Science Immunology summarized the role of resident tissue macrophages (RTMs) in homeostasis and disease.

Study: Resident tissue macrophages: Key coordinators of tissue homeostasis beyond immunity. Image Credit: ART-ur/Shutterstock.comStudy: Resident tissue macrophages: Key coordinators of tissue homeostasis beyond immunity. Image Credit: ART-ur/Shutterstock.com


Macrophages are evolutionarily conserved phagocytes ubiquitously present in almost all organs and tissues. It is recognized that the umbrella term macrophage comprises highly heterogeneous cells with diverse functions and roles.

RTMs are stable, long-lived subpopulations in different organs and tissues and have been linked to innate immunity and the pathogenesis of chronic inflammatory diseases. However, RTMs have broader functions beyond immunity.

Recently, exploring RTM subsets to functional, developmental, and spatial levels has become feasible, helping identify mechanisms of tissue homeostasis.

Notwithstanding these advances, substantial knowledge gaps remain. In the present review, researchers provided insights into conditions impacting RTM identity, division of labor among RTM subsets, and RTM dysfunction in disease.

Tissue microenvironment impacts RTM development

RTMs originate from embryonic progenitors or hematopoietic stem cell (HSC)-derived monocytes. The local microenvironment influences the trajectories of RTM differentiation upon seeding a tissue. In homeostasis, the local environmental cues shape RTM cell identity in a tissue-specific manner.

Further, the phenotypic and functional convergence of HSC-derived monocytes towards a tissue-specific RTM program is driven by the local environment.

However, inflammation or disease markedly impacts their differentiation. During such disturbance, the differentiation of HSC-derived monocytes skews toward pro-reparative, tumor-supportive, or pro-inflammatory phenotypes, differing from that of steady-state RTMs.

These inflammation-associated macrophages (iMacs) are short-lived, and upon resolution (of the disturbance), the tissue transitions to a distinct state, i.e., inflammation aftermath.

There may be permanent changes in the original homeostatic distribution and the composition of environmental factors. This was demonstrated in white adipose tissue, where HSC-derived RTMs acquired a more inflammatory phenotype following the resolution of chronic inflammation.

This post-inflammation scar led to HSC-derived RTMs being unable to differentiate into their original cellular state.

Coexistence of RTM subsets within tissues

Historically, it has been believed that organs and tissues are populated by unique tissue-specific RTMs during homeostasis, such as Langerhans cells in the skin, alveolar macrophages (AMs) in the lungs, Kupffer cells in the liver, and microglia in the brain.

However, a seminal work from 2010 showed that embryonic yolk sac progenitors, not monocytes, give rise to microglia.

This was also instrumental in revealing the embryonic origin of other RTMs. Studies have demonstrated that two distinct conserved RTM subsets populate most tissues in the interstitial space.

The authors term these RTM subsets as perivascular macrophages (PVMs). The PVMs precede with the name of the organ/tissue of residence.

Of the conserved PVM subsets, T cell immunoglobulin and mucin domain containing 4 (TIM4+) PVMs emerge during embryogenesis in multiple organs and are characterized by low levels of major histocompatibility complex II (MHCII) and high levels of TIM4, folate receptor beta (FOLR2), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), and cluster of differentiation 206 (CD206).

By contrast, MHCII+ PVMs emerge from HSC-derived monocytes and are characterized by low/intermediate levels of FOLR2 and LYVE1 and high levels of CD206 and MHCII.

While some studies have observed a C-C motif chemokine receptor 2 (CCR2+) PVM subset, they are likely to be recent organ immigrants. Although some organs have unique tissue-specific subsets of RTMs, almost all organs share these two conserved PVMs.

Division of labor among RTMs

Microglia are the only brain RTM subset in contact with neurons. Several fundamental microglial functions beyond immunity have been uncovered more recently. Animal studies have shown that microglia are essential in neuronal development and fitness.

Microglia secrete growth factors critical for synapse formation. Additionally, they survey the brain microenvironment and modulate neuronal activity through synaptic engulfment and pruning.

Recent studies have revealed the presence of PVMs in perivascular spaces of the central nervous system (CNS). Further, these PVMs regulate cerebrospinal fluid (CSF) dynamics, and TIM4+ PVMs in the brain facilitate proper extracellular matrix (ECM) dynamics.

This idea was corroborated by the findings of abnormal ECM deposition and deterioration of CSF flow dynamics in aged mice, which are linked to a smaller ratio of brain TIM4+-to-MHCII+ PVMs.

The distinct locations of lung PVMs indicate they have specialized roles. For instance, lung MHCII+ PVMs may regulate neuronal interaction with stromal cells, whereas lung TIM4+ PVMs contribute to lung homeostasis.

Besides, lung TIM4+ PVMs may be involved in wound healing, while the MHCII+ counterparts may be involved in antigen presentation and immune activation.

Heart MHCII+ and TIM4+ PVMs produce growth factors to support proper cellular functions and adjust to physiologic demands. Cardiac PVMs are in close contact with cardiomyocytes and participate in mutual electric conduction, supporting normal cardiac contractions.

Gut muscularis MHCII+ and TIM4+ PVMs are close to blood vessels, myenteric plexus, and submucosal plexus. Gut MHCII+ PVMs are closely associated with neuronal bodies of the enteric nervous system.

Mechanistically, gut muscularis PVMs secrete bone morphogenetic protein 2 (BMP2) to regulate enteric neurons expressing the BMP2 receptor. Besides, they regulate gastrointestinal motility independent of the enteric nervous system. Recent studies suggest that gut PVMs promote neuroprotection and limit neuronal cell death.

RTM dysregulation and disease

It is established that HSC-derived iMacs are linked to chronic inflammatory diseases. This chronicity is thought to be due to ongoing inflammation leading to tissue function loss.

Nevertheless, how dysfunction or deviation of RTMs’ core homeostatic functions cause disease remains less studied. Usually, deviation is required for proper tissue repair.

However, it is not clear how long-term and persistent deviation affects tissue physiology and disease severity. Pulmonary alveolar proteinosis is caused by AM dysfunction, characterized by protein and surfactant accumulation in the lung alveolar space, limiting proper gas exchange and increasing susceptibility to infections.

This can occur due to mutations in the granulocyte-macrophage colony-stimulating factor (GM-CSF), autoantibodies against GM-CSF, or silica inhalation. Further, the absence or dysfunction of lung TIM4+ PVMs can result in increased fibrosis and loss of tissue function.

Likewise, dysregulation of heart TIM4+ PVMs exacerbates fibrosis following cardiac infarction. Loss of RTM’s core homeostatic functions may impact cancer development.

A recent study on breast cancer patients showed that those harboring tumors with increased breast TIM4+ PVMs had improved survival rates and T cell priming against the tumor.

This suggested that enhancing the TIM4+ PVMs’ homeostatic functions while inhibiting the activity of HSC-derived tumor-related macrophages can be effective for treatment.

Further, disruption of ECM remodeling in brain PVMs is associated with aging and Alzheimer’s disease (AD).

Concluding remarks

Taken together, ontogeny and local environmental cues shape the phenotype and heterogeneity of RTMs.

There is a strong division of labor among RTM subpopulations. The study proposed a unifying nomenclature for the two conserved RTM subpopulations and explored the roles of several unique tissue-specific RTM subsets in homeostasis and disease.

Nevertheless, further studies are required to delineate how RTM dysfunction leads to chronic inflammatory diseases fully.

Journal reference:
Tarun Sai Lomte

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.


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