The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD

Abstract

Extravasation of monocytes into tissue and to the site of injury is a fundamental immunological process, which requires rapid responses via post translational modifications (PTM) of proteins. Protein arginine methyltransferase 7 (PRMT7) is an epigenetic factor that has the capacity to mono-methylate histones on arginine residues. Here we show that in chronic obstructive pulmonary disease (COPD) patients, PRMT7 expression is elevated in the lung tissue and localized to the macrophages. In mouse models of COPD, lung fibrosis and skin injury, reduced expression of PRMT7 associates with decreased recruitment of monocytes to the site of injury and hence less severe symptoms. Mechanistically, activation of NF-κB/RelA in monocytes induces PRMT7 transcription and consequential mono-methylation of histones at the regulatory elements of RAP1A, which leads to increased transcription of this gene that is responsible for adhesion and migration of monocytes. Persistent monocyte-derived macrophage accumulation leads to ALOX5 over-expression and accumulation of its metabolite LTB4, which triggers expression of ACSL4 a ferroptosis promoting gene in lung epithelial cells. Conclusively, inhibition of arginine mono-methylation might offer targeted intervention in monocyte-driven inflammatory conditions that lead to extensive tissue damage if left untreated.

Targeting ferroptosis as a vulnerability in pulmonary diseases

“…Under the stimulation of CS, macrophages, neutrophils, and lymphocytes are recruited in the small airways and the lung parenchyma to secret inflammatory factors to induce oxidative stress and pulmonary epithelial cells death [ 84 , 85 ]. Among them, the accumulation of monocyte-derived macrophages increases leukotriene B4 (LTB4) secretion and triggers the expression of ACSL4 on epithelial cells, thereby inducing alveolar epithelial type 2 (AT2) cell ferroptosis [ 85 ]. In addition, COPD patients are companied with iron homeostasis imbalance and lipid peroxidation.…”

“…In addition, COPD patients are companied with iron homeostasis imbalance and lipid peroxidation. Under CS exposure, the NOCA4-mediated ferritinophagy pathway and IRP2 upregulated mitochondrial iron overload are initiated, whereas GPX4 related defending pathway is inhibited [ 85 – 87 ].…”

Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy

“…The first kinds of macrophages differentiate themselves during the inflammatory affections. In fact, the abnormal amount of chemokines produced during this pathological alteration, such as IFN-γ, the macrophage colony-stimulating factor (M-CSF), CCL2, CCL5, etc., induced a strong chemo-attraction of circulating monocytes, and after extravasation, they differentiated into macrophages [ 58 , 59 ]. On the other hand, tissue-resident macrophages exist in quite all tissues, e.g., in the liver (Kupffer cells), lung (alveolar macrophages), kidneys (mesangial cells), brain (microglial cells), etc., and contribute actively to the maintenance of homeostasis conditions [ 60 ].…”

Physiological Effects of Ferroptosis on Organ Fibrosis

“…Dihydroquercetin treatment protected against COPD by inhibiting cigarette smoke-induced ferroptosis through the Nrf2-dependent signaling pathway [ 90 ]. Inflammatory macrophage accumulation has been recognized as a key factor involved in the progression of COPD, and mechanistic studies have shown that macrophages induce increased expression of ACSL4 in AT2 cells through arachidonate-5-lipoxygenase-mediated leukotriene B4 release, thereby rendering lung epithelial cells more susceptible to ferroptosis and injury [ 91 ]. These studies suggest that ferroptosis of airway epithelial cells may be an important mechanism underlying the progression of chronic inflammation in individuals with COPD and subsequent changes in airway fibrosis.…”