Pilot, T. | Search bioRxiv

bioRxiv2024

CD226+ adipose tissue macrophages arise from MDP-derived monocytes and regulate lipid metabolism.

Macrophages are innate immune cells present in all tissues, in which they participate in immune responses and maintenance of tissue homeostasis. They develop either from embryonic precursors or from circulating monocytes, and their origin impacts their functions. We previously observed robust recruitment of monocytes to brown adipose tissue in which they could differentiation into two distinct macrophage subsets identifiable by CD206 or CD226 expression. In the present study, we investigated monocyte differentiation pathways in brown adipose tissue and the function of monocyte-derived macrophages. Fate mapping analysis revealed a low contribution of GMP- and a high contribution of MDP-derived monocytes to the CD226high macrophage subset. Importantly, adoptive transfer experiments demonstrate that MDP- but not GMP-derived monocytes are pre-conditioned to give rise to CD226high macrophages. We found that MDP-derived CD226high macrophages were also present in other tissues including peritoneal cavity, adrenal glands and all adipose depots. CD226high macrophages were regulated by both GM-CSF and CSF1R. Genetic depletion of CD226high macrophages caused increased BAT and plasma triglyceride content. We thus identify CD226high MDP-derived macrophages as a new myeloid cell type conserved across tissues and tied to lipid metabolism homeostasis.

immunology↗

bioRxiv2023

Atheroma plaque microenvironment stimulates kynurenine production by macrophages to induce endothelial adhesion molecules in the context of atherogenesis

Cardiovascular diseases, including atherosclerosis, are major causes of morbidity and mortality worldwide. Here, we investigate the role of the kynurenine pathway (KP) in macrophages in the context of atheroma plaque microenvironment and its impact on atherogenesis. Using an in vitro model of primary human macrophages, we observed that exposure to plaque homogenates induces a marked increase in the early steps of the KP which impacts on kynurenine production. This was confirmed by immunostaining on human plaque of carotid arteries. Further investigation into the underlying molecular mechanisms revealed that LXR signaling contributes to this plaque microenvironment-induced KP activation. We showed that kynurenine released from macrophages affected endothelial cells, leading to increased expression of ICAM-1 and VCAM-1 in an AhR-dependent manner. Consistently with the proatherogenic effects, in a cohort of atherosclerotic patients, we observed higher levels of plasma kynurenine in patients with lower extremity arterial disease. In line with the results of in vitro investigations, the plasma kynurenine levels were associated plaque oxysterol content. Using a multiple logistic regression model, we showed that plasma kynurenine was independently associated with lower extremity arterial disease in atherosclerotic patients. Altogether, our data indicate that the activation of KP in macrophages in the context of atheroma plaque is partially mediated by LXR axis and leads to the release of kynurenine. This, in turn, contributes to the exacerbation of both local and peripheral atherosclerosis particularly through the activation of endothelial cells.

immunology↗