ABSTRACT
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.
Subject(s)
Lung/drug effects , Lung/physiology , Lymphotoxin beta Receptor/antagonists & inhibitors , Regeneration/drug effects , Signal Transduction/drug effects , Wnt Proteins/agonists , Adaptive Immunity , Aging/metabolism , Alveolar Epithelial Cells/cytology , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/metabolism , Animals , Apoptosis/drug effects , Emphysema/metabolism , Female , Humans , Immunity, Innate , Lung/metabolism , Lymphotoxin beta Receptor/metabolism , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Pulmonary Disease, Chronic Obstructive/metabolism , Smoke/adverse effects , Stem Cells/drug effects , Stem Cells/metabolism , Wnt Proteins/metabolism , beta Catenin/metabolismABSTRACT
The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the mouse meninges contain a pool of monocytes and neutrophils supplied not from the blood but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation, CNS-infiltrating myeloid cells can originate from brain borders and display transcriptional signatures distinct from their blood-derived counterparts. Thus, CNS borders are populated by myeloid cells from adjacent bone marrow niches, strategically placed to supply innate immune cells under homeostatic and pathological conditions. These findings call for a reinterpretation of immune-cell infiltration into the CNS during injury and autoimmunity and may inform future therapeutic approaches that harness meningeal immune cells.