Iliakis, Chrysante S.; (2025) The interplay between cell origin and lung environment in shaping alveolar macrophage function. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Alveolar macrophages (AMs) are resident sentinels of the airways that support steady-state lung function and play important roles in organ immunity. While the steady-state AM pool is fetally derived in mice (fAMs), during lung insult, infiltrating monocytes can give rise to long-lived bone marrow monocyte-derived AMs (bmAMs) with altered functionality that can impact the outcome of heterologous infection challenges. This thesis investigated the relative contributions of cell origin and recruitment context to the bmAM phenotype through comparative analysis of bmAMs elicited during influenza (flu) infection and following sterile depletion with clodronate liposomes. Despite the different damage and cytokine environments induced, clodronate and flu-elicited bmAMs share several functional characteristics, including a near-identical cytokine secretion profile following restimulation (immunoreactivity), a more glycolytic metabolic profile, and distinct transcriptome and surface phenotype to fAMs. BmAM responsiveness was similar following TLR2, TLR4 and TLR9 stimulation, but flu-elicited bmAMs additionally display enhanced sensitivity to RIGI, TLR3 and IFNAR stimulation. In both contexts, with time spent in the lung, bmAMs progressively resemble fAMs in terms of immunoreactivity and transcriptome (immunosedation). Yet, immunosedation takes three weeks post-clodronate and two months post-flu. Adoptive transfer of AMs shows that immunosedation speed is regulated cell-extrinsically by tonic signals from the lung environment. Integrating AM and epithelial cell transcriptomics with bronchoalveolar lavage fluid proteomics after influenza highlighted differences in type I and II IFN, IL-1 and IL-10 receptor signalling post-infection, which may therefore represent candidate antagonists and drivers of immunosedation. These results highlight that cell origin plays a dominant role in shaping the bmAM phenotype, but that the post-insult lung can further modulate bmAM reactivity at early phases as well as influencing the speed of tissue adaptation at late phases postinfection. Furthermore, this work identifies potential molecular mechanisms regulating bmAM phenotype and function that could be leveraged for therapeutic intervention.

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