Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator of MMP-12 reuptake from broncho-alveolar fluid, driving in two independently generated Trpml3-/- mouse models enlarged lung injury, which is further exacerbated after elastase or tobacco smoke treatment. Mechanistically, using a Trpml3IRES-Cre/eR26-τGFP reporter mouse model, transcriptomics, and endolysosomal patch-clamp experiments, we show that in the lung TRPML3 is almost exclusively expressed in alveolar macrophages, where its loss leads to defects in early endosomal trafficking and endocytosis of MMP-12. Our findings suggest that TRPML3 represents a key regulator of MMP-12 clearance by alveolar macrophages and may serve as therapeutic target for emphysema and chronic obstructive pulmonary disease

Role of PRMT7 in the recruitment of monocyte-derived macrophages into lung tissue and COPD pathogenesis

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide with limited therapeutic options. While cigarette smoke is the main reason of tissue inflammation and destruction in COPD, the regulatory mechanisms underlying the immunological processes still remain unclear. There are multiple factors contributing to the progression of COPD; such as genetics, gender, age, infections and last but not least epigenetics. In recent years, the importance of epigenetics to the pathogenesis of the disease has emerged. Methylation of protein arginine residues is a post-translational modification performing as an epigenetic modulator of many cellular mechanisms including cell signaling, transcription and mRNA processing. More importantly, it has been implicated in immune system dysfunction and inflammation. In this study, it is reported that the expression of one member of the protein arginine methyltransferase (PRMT) enzyme family, PRMT7, is enriched in the lungs of COPD patients and that this correlates with disease severity. Interestingly, the major cell type in the lung, which predominantly expressed PRMT7, is found to be macrophages. The expression of PRMT7 in monocytes and macrophages increases with inflammatory insult through NF-κB/RelA signaling. In parallel, PRMT7 is demonstrated to be essential for monocyte-driven macrophage accumulation in the development of COPD and fibrosis. Under inflammatory conditions, the extravasation of monocytes into tissues is a fundamental immunological process, crucially dependent upon trans-endothelial migration from blood vessels into inflamed tissues with the subsequent differentiation into macrophages initiating and perpetuating disease pathogenesis. In COPD, fibrosis and skin injury mouse models, mice with reduced expression of PRMT7 are protected against disease development as recruitment of monocyte derived-pro-inflammatory macrophages to the site of injury is impaired. Additionally, CRISPR/Cas9-targeted knockout of PRMT7 reveals a mechanism whereby mono-methylation of histone proteins regulate RAP1 mediated MAPK signaling and subsequent migration and adhesion ability. Thus, targeted inhibition of PRMT7 induced mono-methylation offers novel therapeutic potential against COPD and other monocyte driven chronic inflammatory conditions.Die chronisch obstruktive Lungenerkrankung (COPD) ist weltweit die dritthäufigste Todesursache mit begrenzten therapeutischen Möglichkeiten. Obwohl Zigarettenrauch die Hauptursache für Gewebeentzündung und -zerstörung bei COPD ist, sind die regulatorischen Mechanismen, die den immunologischen Prozessen zugrunde liegen, noch immer unklar. Es gibt mehrere Faktoren, die zur Entstehung von COPD beitragen; dazu gehören Genetik, Geschlecht, Alter, Infektionen und nicht zuletzt die Epigenetik. In den letzten Jahren hat sich die Bedeutung der Epigenetik für die Pathogenese der Krankheit herauskristallisiert. Die Methylierung von Protein-Arginin-Resten ist eine posttranslationale Modifikation, die als epigenetischer Modulator vieler zellulärer Mechanismen einschließlich der Zellsignalisierung, Transkription und mRNA-Verarbeitung fungiert. Noch wichtiger ist, dass sie an Funktionsstörungen des Immunsystems und Entzündungen beteiligt ist. In dieser Studie wird berichtet, dass die Expression eines Mitglieds der Protein-Arginin-Methyltransferase (PRMT)-Enzymfamilie, PRMT7, in den Lungen von COPD-Patienten angereichert ist und dass dies mit dem Schweregrad der Krankheit korreliert. Interessanterweise stellte sich heraus, dass der wichtigste Zelltyp in der Lunge, der PRMT7 vorwiegend exprimiert, Makrophagen sind. Die Expression von PRMT7 in Monozyten und Makrophagen nahm bei entzündlichem Befund durch NF-κB/RelA-Signalisierung zu. Parallel dazu wurde nachgewiesen, dass PRMT7 für die monozytengesteuerte Makrophagenakkumulation bei der Entwicklung von COPD und Fibrose wesentlich ist. Unter entzündlichen Bedingungen ist die Extravasation von Monozyten in Gewebe ein grundlegender immunologischer Prozess, der entscheidend von der trans-endothelialen Migration von Blutgefäßen in entzündetes Gewebe abhängt. In COPD-, Fibrose- und Hautverletzungs-Mausmodellen waren Mäuse mit reduzierter Expression von PRMT7 vor der Krankheitsentstehung geschützt, da die Rekrutierung von pro-inflammatorischen Makrophagen an der Verletzungsstelle beeinträchtigt war. Darüber hinaus zeigte der CRISPR/Cas9-gerichtete Knock-out von PRMT7 einen Mechanismus, bei dem die Monomethylierung von Histonproteinen, die RAP1 regulierten, das MAPK-Signal und die nachfolgende Migrations- und Adhäsionsfähigkeit vermittelte. Somit bietet die gezielte Hemmung der durch PRMT7 induzierten Monomethylierung ein neues therapeutisches Potenzial gegen COPD und andere monozytengesteuerte chronische Entzündungszustände

Inhibition of LTβR-signalling activates Wnt-induced regeneration in lung

Lymphotoxin β-receptor (LTβR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures1,2, which are associated with severe chronic inflammatory diseases that span several organ systems3-6. How LTβR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTβR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTβR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTβR target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LTβR signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LTβR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFβ signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/β-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTβR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies