Sapey, E. | bioRxiv Science

bioRxiv2026

Macrophage Phagocytic Impairment is associated with Dysbiosis of the Respiratory Microbiome in Frail older adults

Advanced age and frailty are risk factors for pulmonary infections, which are the leading cause of death in older adults. The mechanism behind increased susceptibility to infection is poorly understood, but interactions between innate immunity and the respiratory microbiome may be implicated. We investigated changes to monocyte-derived macrophage function, and the respiratory microbiome in healthy young adults, healthy older adults, and frail older adults. We found that macrophage phagocytosis and efferocytosis is impaired in frail older adults, associated with elevated pro-inflammatory cytokine secretion and a failure to regulate expression of phagocytic receptors CD14 and CD36. Pre-treatment of macrophages with a PPAR{gamma} agonist restored phagocytosis, implicating this pathway in cellular dysfunction. Accompanying respiratory microbiome showed reduced bacterial diversity and richness in older adults, which was more advanced in frail older adults. These results are consistent with a macrophage predation defect in the lungs during frailty which may impact bacterial diversity, and may be improved via manipulation of the PPAR{gamma} pathway. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/703495v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1c53e8forg.highwire.dtl.DTLVardef@8e34bcorg.highwire.dtl.DTLVardef@28345dorg.highwire.dtl.DTLVardef@185d93d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Neutrophil and NET-driven pulmonary microvascular injury following myocardial injury: attenuation by S100A8/A9 inhibition

Myocardial infarction (MI) triggers not only local cardiac damage but also a systemic inflammatory response that extends to remote organs. The pulmonary microcirculation, by virtue of its dense capillary network and direct anatomical proximity to the heart, is particularly vulnerable. Neutrophils and their effector mechanisms, including neutrophil extracellular traps (NETs) and the alarmin S100A8/A9, have been implicated in adverse cardiovascular outcomes. However, their role in remote damage post-MI remains unclear. Using intravital in vivo imaging in murine MI models and analysis of human lung tissues, we show that MI induces rapid pulmonary neutrophil and platelet recruitment, formation of platelet-neutrophil aggregates within capillaries, and endothelial activation. These changes are accompanied by NET release, fibrin deposition, and microvascular obstruction, leading to impaired vascular perfusion and necrosis. These pulmonary disturbances closely parallel those in the infarcted myocardium and exceed responses observed in other organs such as the kidney and liver, highlighting the lung as a vulnerable target organ. Increased neutrophil recruitment was associated with marked upregulation of the neutrophil-derived, NET-associated alarmin S100A8/A9 in mouse and human lungs, where it co-localised with infiltrating neutrophils, NETs, and platelet aggregates. Additionally, we show that short-term pharmacological inhibition of S100A8/A9 with ABR-238901 significantly attenuated pulmonary neutrophil infiltration, reduced NETosis and fibrin deposition, and restored capillary perfusion while rebalancing the pulmonary immune landscape. Together, these findings identify the lung as a principal site of remote thrombo-inflammatory injury after MI and implicate S100A8/A9, a neutrophil-derived, NET-associated alarmin, as a mechanistic driver of pulmonary microvascular dysfunction. We propose that targeting this pathway could provide dual protection for both cardiac and pulmonary microcirculations in the acute phase of myocardial injury. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/675647v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@289725org.highwire.dtl.DTLVardef@db2011org.highwire.dtl.DTLVardef@16790dorg.highwire.dtl.DTLVardef@1655b17_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗