RESUMEN
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.
Asunto(s)
Proteína-Arginina N-Metiltransferasas , Enfermedad Pulmonar Obstructiva Crónica , Animales , Arginina/metabolismo , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Monocitos/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/genéticaRESUMEN
Lymphotoxin ß-receptor (LTßR) 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 LTßR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTßR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTßR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTßR 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 LTßR 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 LTßR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFß signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/ß-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTßR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies.
Asunto(s)
Pulmón/efectos de los fármacos , Pulmón/fisiología , Receptor beta de Linfotoxina/antagonistas & inhibidores , Regeneración/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteínas Wnt/agonistas , Inmunidad Adaptativa , Envejecimiento/metabolismo , Células Epiteliales Alveolares/citología , Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Animales , Apoptosis/efectos de los fármacos , Enfisema/metabolismo , Femenino , Humanos , Inmunidad Innata , Pulmón/metabolismo , Receptor beta de Linfotoxina/metabolismo , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Humo/efectos adversos , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide with no curative therapy. A non-canonical Notch ligand, DNER, has been recently identified in GWAS to associate with COPD severity, but its function and contribution to COPD is unknown. METHODS: DNER localisation was assessed in lung tissue from healthy and COPD patients, and cigarette smoke (CS) exposed mice. Microarray analysis was performed on WT and DNER deficient M1 and M2 bone marrow-derived macrophages (BMDM), and gene set enrichment undertaken. WT and DNER deficient mice were exposed to CS or filtered air for 3â¯day and 2â¯months to assess IFNγ-expressing macrophages and emphysema development. Notch and NFKB active subunits were quantified in WT and DNER deficient LPS-treated and untreated BMDM. FINDINGS: Immunofluorescence staining revealed DNER localised to macrophages in lung tissue from COPD patients and mice. Human and murine macrophages showed enhanced DNER expression in response to inflammation. Interestingly, pro-inflammatory DNER deficient BMDMs exhibited impaired NICD1/NFKB dependent IFNγ signalling and reduced nuclear NICD1/NFKB translocation. Furthermore, decreased IFNγ production and Notch1 activation in recruited macrophages from CS exposed DNER deficient mice were observed, protecting against emphysema and lung dysfunction. INTERPRETATION: DNER is a novel protein induced in COPD patients and 6â¯months CS-exposed mice that regulates IFNγ secretion via non-canonical Notch in pro-inflammatory recruited macrophages. These results provide a new pathway involved in COPD immunity that could contribute to the discovery of innovative therapeutic targets. FUNDING: This work was supported from the Helmholtz Alliance 'Aging and Metabolic Programming, AMPro'.
Asunto(s)
Interferón gamma/biosíntesis , Macrófagos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Receptores de Superficie Celular/metabolismo , Receptores Notch/metabolismo , Animales , Biomarcadores , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Expresión Génica , Humanos , Inmunofenotipificación , Activación de Macrófagos/genética , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Ratones , Ratones Noqueados , Modelos Biológicos , Monocitos/inmunología , Monocitos/metabolismo , Proteínas del Tejido Nervioso/genética , Enfermedad Pulmonar Obstructiva Crónica/etiología , Receptores de Superficie Celular/genética , Transducción de SeñalRESUMEN
Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism.