Molecule Allowing for Macrophages to Die as Intended Might Treat IPF

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by Marta Figueiredo PhD |

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Blocking the activity of a cell death-suppressing protein called Bcl-2 promoted the death of macrophages — a type of immune cell involved in pulmonary fibrosis (PF) — and reversed established lung scarring in a mouse model, a study showed.

Notably, Bcl-2’s anchoring at the surface of macrophage mitochondria was found to be behind the cells’ previously reported resistance to programed cell death (apoptosis) in PF. (Mitochondria are small organelles inside cells involved in energy production and in the activation of apoptosis.)

These findings highlight the damaging role of macrophages in lung fibrosis, and point to macrophage Bcl-2 as a potential therapeutic target for PF, the researchers noted.

The study, “Targeting Cpt1a-Bcl-2 interaction modulates apoptosis resistance and fibrotic remodeling,” was published in the journal Cell Death & Differentiation.

Idiopathic pulmonary fibrosis (IPF), a form of PF with no clear cause, is characterized by abnormal remodeling of lung tissue that leads to fibrosis, or tissue scarring, and increased stiffness, making it difficult for patients to breathe.

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Previous research suggested that IPF is driven by injury and apoptosis of alveolar epithelial cells, the cells that line the tiny air sacs in the lungs where gases are exchanged.

In turn, the disease is also associated with apoptosis resistance in fibroblasts — connective tissue cells that are often considered the main drivers of lung fibrosis — and in macrophages, a type of immune cell that can produce a major pro-fibrotic molecule called TGF-beta 1.

However, the mechanisms by which this apoptosis resistance occurs in lung macrophages remains poorly understood.

A team of researchers at the University of Alabama at Birmingham shed light on the underlying mechanisms of this resistance, and subsequently identified a new potential target for treating lung fibrosis.

They first found that levels of Bcl-2, a protein that suppresses apoptosis, were nearly four times higher in mitochondria of lung macrophages collected from IPF patients than levels seen in those from healthy individuals.

Notably, mitochondrial Bcl-2 was also at higher-than-normal levels in lung macrophages from a mouse model of IPF — and similar, abnormal increases in two other mitochondrial proteins, called mitochondrial calcium uniporter (MCU) and carnitine palmitoyltransferase 1a (Cpt1a), were further observed.

MCU is a protein channel that enables calcium ions to enter mitochondria, while Cpt1a — located at the surface of mitochondria — is the rate-limiting enzyme for fatty acid oxidation (FAO), a metabolic process that allows mitochondria to produce energy by breaking down fatty molecules.

MCU was previously shown to regulate metabolic reprogramming to FAO in lung macrophages of a mouse model of IPF, and this event promoted lung fibrosis.

Further analyses in mice and lab-grown mouse lung cells revealed that MCU regulated Bcl-2 in the mitochondria of lung macrophages by increasing Cpt1a’s activity, and promoting its direct binding to Bcl-2 at the surface of mitochondria.

It was this interaction between Cpt1a and Bcl-2 that anchored the apoptosis-suppressing protein to mitochondria, reducing this programmed death process of lung macrophages.

These results indicate that “Cpt1a-Bcl-2 binding is required for recruitment and apoptosis resistance in [lung macrophages],” the researchers wrote.

Moreover, both the genetic deletion of Bcl-2 in macrophages and overall pharmacological suppression of Bcl-2 reversed established lung fibrosis in the mouse model, supporting macrophage Bcl-2 as a “novel therapeutic target to attenuate fibrotic remodeling in the lung.”

Pharmacological blocking of Bcl-2 was achieved with oral administration of ABT-199, a Bcl-2 suppressor approved to treat certain blood cancers (sold by AbbVie and Genentech under the brand name Venclexta). In this study, ABT-199 was found to completely block Cpt1a–Bcl-2 interaction.

These findings highlight “a unique relationship between metabolic reprogramming to FAO and apoptosis resistance in fibrosis progression,” the researchers wrote.

While ABT-199 increased apoptosis in alveolar epithelial cells (AECs), it was the induction of death in macrophages, and possibly fibroblasts, that reversed the animal’s lung fibrosis. This indicated that “AEC apoptosis, alone, does not induce fibrosis and requires other cells, specifically [lung macrophages], to mediate fibrotic remodeling,” the team noted.

“Taken together, these observations suggest that FAO provokes apoptosis resistance through the stabilization of Bcl-2 in the mitochondria by binding to Cpt1a,” the researchers wrote.

Moreover, they demonstrate that lung macrophages “are required for fibrosis progression, and they suggest a novel therapeutic target to prevent progressive aberrant fibrotic remodeling,” they wrote.

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