Biology subjects

Ngai, D.

Publications and source records attributed to Ngai, D..

2 recordsLinked to original sources

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

Efferocytosis-Induced Lactate Enables the Proliferation of Pro-Resolving Macrophages to Mediate Tissue Repair

The clearance of apoptotic cells (ACs) by macrophages (efferocytosis) promotes tissue repair by preventing necrosis and inflammation and by activating pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which AC-derived nucleotides trigger Myc-mediated macrophage proliferation, thereby increasing the pool of efferocytosis-competent macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably, efferocytosis-induced lactate production. While the AC-nucleotide pathway leads to induction of Myc mRNA, lactate signaling is required for the stabilization of Myc protein and subsequent macrophage proliferation. Lactate, via GPR132 and protein kinase A, activates AMP kinase, which increases the NAD+:NADH ratio. This upstream pathway then activates the NAD+-dependent protein deacetylase, SIRT1, which deacetylates Myc to promote its stabilization. Inhibition or silencing of any step along this pathway prevents the increase in Myc protein and proliferation in efferocytosing macrophages despite the presence of the AC-nucleotide/Myc mRNA pathway. To test importance in vivo, we transplanted mice with bone marrow cells in which the lactate biosynthetic enzyme lactate dehydrogenase A (LDHA) was knocked down. We then subjected these mice and control bone marrow-transplanted mice to dexamethasone-induced thymocyte apoptosis, a model of high-AC burden. The thymi of the LDHA-knockdown cohort showed reduced macrophage Myc protein expression and proliferation, impaired AC clearance, and increased tissue necrosis. Thus, efferocytosis-induced macrophage proliferation, which is a key process in tissue resolution, requires inputs from two independent efferocytosis-induced processes: a signaling pathway induced by AC-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.

immunology↗