The guardians of pulmonary harmony: alveolar macrophages orchestrating the symphony of lung inflammation and tissue homeostasis

Abstract

Recent breakthroughs in single-cell sequencing, advancements in cellular and tissue imaging techniques, innovations in cell lineage tracing, and insights into the epigenome collectively illuminate the enigmatic landscape of alveolar macrophages in the lung under homeostasis and disease conditions. Our current knowledge reveals the cellular and functional diversity of alveolar macrophages within the respiratory system, emphasising their remarkable adaptability. By synthesising insights from classical cell and developmental biology studies, we provide a comprehensive perspective on alveolar macrophage functional plasticity. This includes an examination of their ontology-related features, their role in maintaining tissue homeostasis under steady-state conditions and the distinct contribution of bone marrow-derived macrophages (BMDMs) in promoting tissue regeneration and restoring respiratory system homeostasis in response to injuries. Elucidating the signalling pathways within inflammatory conditions, the impact of various triggers on tissue-resident alveolar macrophages (TR-AMs), as well as the recruitment and polarisation of macrophages originating from the bone marrow, presents an opportunity to propose innovative therapeutic approaches aimed at modulating the equilibrium between phenotypes to induce programmes associated with a pro-regenerative or homeostasis phenotype of BMDMs or TR-AMs. This, in turn, can lead to the amelioration of disease outcomes and the attenuation of detrimental inflammation. This review comprehensively addresses the pivotal role of macrophages in the orchestration of inflammation and resolution phases after lung injury, as well as ageing-related shifts and the influence of clonal haematopoiesis of indeterminate potential mutations on alveolar macrophages, exploring altered signalling pathways and transcriptional profiles, with implications for respiratory homeostasis.

FIGURE 1

Illustration capturing the molecular pathways and cellular insights during lung homeostasis, regeneration/repair and the indicated pathological conditions. a) Homeostasis: on tissue-resident alveolar macrophages (TR-AMs) intricately preserve alveolar homeostasis through local proliferation, adeptly clearing apoptotic cells, proteins and phospholipids in response to microenvironmental challenges. Alveolar epithelial cell (AEC) type II (oxidative phosphorylation (OXPHOS)) orchestrate granulocyte–macrophage colony-stimulating factor (GM-CSF) regulation, a pro-survival signalling for TR-AMs, finely tuning surfactant accumulation. The interplay among AEC I, AEC II and TR-AMs is central. Airway epithelium modulates macrophages via interactions with cluster of differentiation (CD)200 and transforming growth factor (TGF)-β imparting sophistication to pulmonary microenvironment dynamics. b) Regeneration/repair: in the reparative phase, macrophages terminate inflammation and coordinate repair processes in response to specific epithelial and ILC2 (innate lymphocyte cells type 2) derived signals (interleukin (IL)-33, IL-4, IL-13). Alveolar macrophages engage in efferocytosis and produce pro-inflammatory mediators such as epiregulin, amphiregulin and placenta-expressed transcript 1 (Plet1). Pro-inflammatory bone marrow-derived macrophages (BMDMs) transit towards a pro-repair phenotype and contribute to epithelial cell proliferation and differentiate into TR-AMs as homeostasis is restored. c) Inflammation: affects lung structural cell interaction with alveolar macrophages, instigating innate and acquired immune responses. Manifestations include leukocyte infiltration and increased pro-inflammatory cytokines, exacerbating inflammation and causing lung alveoli damage. Recruited BMDMs exert a robust inflammatory response, illustrating dynamic modulation during inflammation and injury. d) Fibrosis/ageing: sustained inflammation or defective epithelial repair can trigger progressive fibrogenesis, causing epithelial and endothelial damage, myofibroblast abundance, and excessive collagen matrix formation. Pro-fibrotic BMDMs are mainly recruited through a chemokine (C–C motif) ligand (CCL)2/C–C chemokine receptor (CCR)2 pathway and their expression patterns induce fibroblast recruitment and activation and excessive production of collagen fibres in the fibrotic niche where the presence of inflammatory BMDMs aggravates tissue damage potentiating the fibrotic process. Pro-fibrotic BMDMs can also directly contribute to collagen production by upregulation of Fra-2 transcription factor and tissue inhibitor of metalloproteinases (TIMP). Accumulation of pro-fibrotic BMDMs may reflect an impaired transition towards a full TR-AM phenotype sustaining the pro-fibrotic process. Ageing induces parallel processes of macrophage maturation and cellular senescence. The aged lung experiences mechanical and physiological changes. Senescent cell accumulation and the senescence-associated secretory phenotype contribute to pro-inflammatory mediator release. Despite increased inflammatory factors, ageing leads to reduced phagocytic capacity in macrophages, with attenuated functional reflecting inflammageing factors such as tumour necrosis factor (TNF)-α, IL-1β and IL-6. Figure partially created with BioRender. CX3CR1: CX3C motif chemokine receptor 1; CXCR: C-X-C chemokine receptor; Ear1: eosinophil-associated, ribonuclease A family, member 1; HIF1: hypoxia-inducible factor 1; IFN: interferon; Irg1: immune responsive gene1; LB: lamellar body; Ly6c: lymphocyte antigen 6 family member C; MARCO: macrophage receptor with collagenous structure; MerTK: tyrosine-protein kinase Mer; PDGF: platelet-derived growth factor; PPARγ: peroxisome proliferator-activated receptor gamma; SASP: senescence-associated secretory phenotype; TFF: trefoil factor family; VEGF: vascular endothelial growth factor; SiglecF: sialic acid binding Ig-like lectin F; HLA: human leukocyte antigen; ATP: adenosine triphosphate; IGF: insulin-like growth factor.