Aging-Associated CCL8+ Senescent Macrophages Recruit CCR1+ Neutrophils to Promote NETs Formation and Impair Meningeal Lymphatic Drainage.

Abstract

Meningeal lymphatic vessels (mLVs) are essential for central nervous system (CNS) waste clearance and brain homeostasis, yet their functional decline during aging remains poorly understood. Here, through integrated single-cell and bulk transcriptomic analyses, we identify a distinct macrophage subset characterized by high CCL8 expression (CCL8⁺ macrophages) that accumulates in aged meninges and exhibits a pronounced senescence-associated secretory phenotype (SASP). Trajectory analysis positions CCL8⁺ macrophages at a senescence-associated terminal differentiation state. Mechanistically, CCL8⁺ macrophages engage in pro-inflammatory crosstalk with neutrophils via the CCL8-CCR1 axis, promoting aberrant neutrophil recruitment and excessive neutrophil extracellular traps (NETs) formation within meningeal lymphatic niches. These NETs structurally and functionally impair meningeal lymphatic drainage. Importantly, pharmacological inhibition of CCR1 with BX471 or enzymatic degradation of NETs with DNase I restores meningeal lymphatic function and ameliorates spatial learning and memory deficits in aged mice. Notably, CCR1 antagonist BX471 has previously been evaluated in early human clinical trials and shown favorable tolerability, supporting the translational feasibility of targeting this pathway. In addition, machine learning approaches identify a robust predictive gene signature associated with this senescent macrophage phenotype. Collectively, our findings reveal a previously unrecognized macrophage-neutrophil-NETs axis that links meningeal immunosenescence to meningeal lymphatic dysfunction and cognitive decline and may represent a promising therapeutic target for aging-related neurodegenerative disorders.