DOI: 10.1161/atvbaha.126.325444 ISSN: 1079-5642

Novel Mechanometabolic Signaling Cascade Linking Efferocytosis to Inflammation Resolution

Dhananjay Kumar, Rajan Pandit, Louise Frausto, Theresea-Anne Governale, Shuai Yuan, Javier Nion Fieira, Abraham Quaye, Kyle McGee, Sandeep Das, Sumit Kumar Anand, Nilesh Pandey, Harpreet Kaur, Tanvir Ahmed, Yash Katakia, Katie Gomez, Braedyn Gates, Luke White, Charlotte Orr, Nora Sperfslage, Matthew W. Breitzman, Lucas J. Showman, Amanda C. Doran, Adam C. Straub, Babak Razani, Matthew D. Woolard, Kasi Lively, Frederick W. Knight, James G. Traylor, Miles A. Sugar, Nirav Dhanesha, Christopher B. Pattillo, A. Wayne Orr, Oren Rom, Arif Yurdagul
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BACKGROUND:

Apoptotic cell clearance by macrophages, termed efferocytosis , resolves inflammation and promotes tissue repair, whereas defective efferocytosis contributes to chronic inflammatory diseases such as atherosclerosis. Putrescine biosynthesis, driven by the rate-limiting enzyme ODC1 (ornithine decarboxylase 1), has emerged as a key efferocytosis-induced metabolic pathway that promotes inflammation resolution. However, the mechanisms regulating ODC1 during atherosclerosis remain undefined. Here, we investigated the mechanisms controlling ODC1 and putrescine biosynthesis and identified a novel integrin αv–FAK (focal adhesion kinase)–Rac1 (Rac family small GTPase 1)–STAT3 (signal transducer and activator of transcription 3)–MYC (MYC proto-oncogene) signaling axis that becomes progressively impaired during atherosclerosis.

METHODS:

We performed metabolomic and cytokine profiling of human atherosclerotic plaques and assessed ODC1 expression in lesional macrophages from humans and mice. Mechanistic studies used apoptotic cell– or polystyrene bead–exposed macrophages, Ldlr –/ – mice with hematopoietic integrin αv deficiency fed a Western-type diet, single-nuclei RNA sequencing, and bulk RNA sequencing.

RESULTS:

Putrescine levels negatively correlated with inflammatory mediators, and ODC1 expression in lesional macrophages declined with disease progression in humans and mice. Engulfment of apoptotic cells or polystyrene beads increased ODC1 expression through an integrin αv– and actin polymerization–dependent mechanism. Hematopoietic integrin αv deficiency exacerbated lesion size and necrosis, reduced efferocytosis, and decreased fibrous cap thickness. Single-nuclei RNA sequencing showed no changes in lesional cell composition but revealed activation of inflammatory pathways specifically in integrin αv–deficient macrophages. Mechanistically, phagocytosis-induced ODC1 expression relied on integrin αv–mediated STAT3 activation and MYC-dependent Odc1 transcription. Bulk RNA sequencing showed that apoptotic cell–exposed human macrophages lacking integrin αv upregulated atherogenic mediators and inflammatory pathways, an effect reversed by restoring putrescine levels.

CONCLUSIONS:

Together, these findings uncover a previously unrecognized mechanistic link between phagocytosis and macrophage metabolism, which we identify as a case of mechanometabolism, and demonstrate how its dysregulation compromises inflammation resolution and promotes atherosclerosis.

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