Alveolar macrophage cell surface receptor TREM2 promotes lung fibrosis

BIRMINGHAM, Ala. – Lung macrophages play a pivotal role in diseases like idiopathic pulmonary fibrosis. Two types of macrophages — the white blood cells that defend the body by killing microbes, removing dead cells and stimulating immune responses — are found in the lung. They are tissue resident macrophages, which are present from birth, and monocyte-derived macrophages that enter the lungs for a short time in response to damage or infection.

Recently these monocyte-derived alveolar macrophages, or Mo-AMs, were identified as key drivers of lung fibrosis disease progression. However, the mechanisms of their pro-fibrotic behavior and survival in the lungs remained unclear, so clinicians continue to lack effective therapies.

In a study published in the journal Nature Communications, Gang Liu, M.D., Ph.D., Huachun Cui, Ph.D., and their University of Alabama at Birmingham colleagues show that TREM2, a cell surface receptor protein on Mo-AM cells, is a critical regulator of macrophage-mediated lung fibrosis. This makes it a promising therapeutic target for intervention, says Gang, a professor in the UAB Department of Medicine Division of Pulmonary, Allergy and Critical Care Medicine.

“We have found an important mechanism by which these Mo-AM cells promote lung fibrogenesis,” Liu said. “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.”

Serious chronic lung fibrosis like idiopathic pulmonary fibrosis is marked by increasing difficulty to breathe.

The UAB researchers showed that TREM2 — which stands for triggering receptors expressed on myeloid cells 2 — is predominantly expressed on monocyte-derived alveolar macrophages in bleomycin-induced fibrotic mouse lungs. They also found that TREM2 was significantly elevated on lung macrophages from patients with idiopathic pulmonary fibrosis.

When Mo-AMs enter the lung in response to lung injuries, they encounter a new environment where they can fight disease or damage yet gradually decline in numbers through the programmed cell death called apoptosis.

However, TREM2 expression on Mo-AMs appears to delay that apoptosis and promote fibrosis. The UAB researchers showed this using deletion mutants or knockdown of the TREM2 receptor. They found that deletion or knockdown disrupted intracellular survival signaling in the Mo-AMs, promoted macrophage apoptosis and attenuated the pro-fibrotic phenotype of the Mo-AMs.

The lung environment for Mo-AMs also differs by presence of lipids in the slippery lung surfactant that prevents lung collapse. Many of these lipid mediators are known to bind tightly with the TREM2 receptor. Liu and colleagues showed that the binding of several lipid mediators to Mo-AMs TREM2 enhanced survival and activity of the macrophages.

Furthermore, ablation of TREM2 or blocking the cell receptor in two different ways — using soluble fragments of the TREM2 receptor to bind lipids before they can find the TREM2 receptors on Mo-AMs or using specific antibodies against TREM2 that prevent binding of lipids to the TREM2 receptors — effectively alleviated lung fibrosis in mice. The antibody treatment was effective even when started one day or one week after the bleomycin treatment that initiates the mouse lung fibrosis.

Thus, TREM2 blocking may be a novel and effective strategy for lung fibrosis, Liu says.

Cui and Sami Banerjee, UAB Department of Medicine Division of Pulmonary, Allergy and Critical Care Medicine, are co-first authors, and Liu is corresponding author of the study, “TREM2 promotes lung fibrosis via controlling alveolar macrophage survival and pro-fibrotic activity.” Other co-authors are Na Xie, Musaddique Hussain, Ashish Jaiswal, Hongli Liu, Tejaswini Kulkarni, Veena B. Antony and Rui-Ming Liu, UAB Department of Medicine Division of Pulmonary, Allergy and Critical Care Medicine; and Marco Colonna, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.

At UAB, Medicine is a department in the Marnix E. Heersink School of Medicine.