Doviak, H. | bioRxiv Science

bioRxiv2026

Transient efferocytosis-induced activation of IKKβ reprograms macrophages to promote tissue resolution

The clearance of apoptotic cells by macrophages, termed efferocytosis, reprograms macrophages to a resolution/repair phenotype, and pathologic defects in efferocytosis drive many chronic inflammatory diseases. Previous studies have elucidated numerous downstream pro-resolving pathways activated by efferocytosis, but whether there exists a common upstream trigger of these pathways remains unknown. Here, we report that efferocytosing macrophages surprisingly use a signaling module typically associated with inflammation to carry out this key initiating role in tissue resolution. The binding of apoptotic cells to the MerTK receptor triggers a rapid and transient activation of inhibitor of nuclear factor (NF) kappa-B kinase subunit beta (IKK{beta}), leading to NF{kappa}B and p38-signal transducer and activator of transcription 3 (STAT3) signaling and then activation of several key downstream pro-resolving pathways, including interleukin-10 (IL-10) production, continuing efferocytosis, and regulatory T (Treg) cell expansion. The upstream IKK{beta} pathway and the downstream resolution pathways are linked through several intermediary molecules, including the transcription factor Myc, the epigenetic modifier ten-eleven translocation-2 (TET2), and the immune checkpoint protein programmed cell death ligand 1 (PD-L1). Deletion of macrophage IKK{beta} in vivo blocks the above resolution pathways and compromises tissue repair in two efferocytosis-mediated repair settings: resolution of thymic injury after dexamethasone-induced thymocyte apoptosis; and, most importantly, atherosclerosis regression induced by low-density lipoprotein (LDL)-lowering, which is highly relevant to the prevention of cardiovascular disease in humans. These findings illustrate the existence of a unifying upstream signal for efferocytosis-induced resolution, which could suggest new therapeutic strategies to enhance multiple tissue resolution pathways and to optimize anti-inflammatory therapies by avoiding blocking IKK{beta}-NF{kappa}B/p38-mediated resolution.

immunology↗

bioRxiv2023

Mouse Model of Heart Attack and Stroke Shows Improved Survival with MPO Inhibition

Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide1. Unfortunately, the lack of a mouse model that develops advanced coronary atherosclerosis and that exhibits a high incidence of spontaneous plaque rupture with MI or stroke has greatly stymied development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Herein, we describe a novel mouse model that develops widespread advanced atherosclerosis including in coronary, brachiocephalic, and carotid arteries. These mice show high mortality following Western Diet feeding with clear evidence of plaque rupture, MI, and stroke. To validate the utility of this model, mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme primarily produced by activated neutrophils and predictive of rupture of human atherosclerotic lesions2-7. AZM198 treatment resulted in marked improvements in survival with a greater than 60% decrease in the incidence of plaque rupture, MI, and stroke. In summary, our work describes a novel mouse model that closely replicates late-stage clinical events of advanced human atherosclerotic disease and evidence that this model can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.

physiology↗