Macrophages use apoptotic cell-derived methionine and DNMT3A during efferocytosis to promote tissue resolution

Abstract

Efferocytosis, the clearance of apoptotic cells (ACs) by macrophages, is critical for tissue resolution, with defects driving many diseases. Mechanisms of efferocytosis-mediated resolution are incompletely understood. Here, we show that AC-derived methionine regulates resolution through epigenetic repression of the ERK1/2 phosphatase Dusp4. We focus on two key efferocytosis-induced pro-resolving mediators, PGE2 and TGFβ1, and show that efferocytosis induces Ptgs2/COX2, leading to PGE2 synthesis and PGE2-mediated induction of TGFβ1. ERK1/2 phosphorylation/activation by AC-activated CD36 is necessary for Ptgs2 induction, but this is insufficient owing to an ERK-DUSP4 negative-feedback pathway that lowers phospho-ERK. However, subsequent AC engulfment and phagolysosomal degradation repress Dusp4, enabling enhanced phospho-ERK and induction of the Ptgs2-PGE2-TGFβ1 pathway. Mechanistically, AC-derived methionine is converted to S-adenosylmethionine (SAM), which is used by DNA-methyltransferase-3A (DNMT3A) to methylate Dusp4. Bone-marrow DNMT3A deletion in mice blocks COX2/PGE2, TGFβ1, and resolution in sterile-peritonitis, apoptosis-induced thymus injury, and atherosclerosis. Knowledge of how macrophages use AC-cargo and epigenetics to induce resolution provides mechanistic insight and therapeutic options for diseases driven by impaired resolution.

Mechanisms of efferocytosis in determining inflammation resolution: Therapeutic potential and the association with cardiovascular disease

“…As described above, Ampomah et al (2022) reported that efferocytosis induces PGE2 production through the CD36/ERK/Ptgs2/COX2 pathway and that PGE2 could further induce TGF‐β synthesis through the EP 2/4 , receptors, contributing to the regression of atherosclerosis. In addition, the protective role of PGE2 and TGF‐β in atherosclerosis has also been reported in several other studies, and the mechanisms are associated with anti‐inflammatory and proresolving properties (Tajbakhsh et al, 2018; Weinstock et al, 2021).…”

“…In zebrafish, after tailfin amputation, macrophage clearance of ACs contributes to the production of PGE2, which drives neutrophil removal via the promotion of reverse migration through EP4 receptors and results in the resolution of inflammation (Loynes et al, 2018). In addition, PGE2 is a positive upstream molecule of TGF‐β, and as described above in this review, efferocytosis can mediate TGF‐β via the Ptgs2/COX2 pathway (Ampomah et al, 2022). In summary, efferocytosis has a powerful ability to metabolize AC‐debris and subsequently to produce PGE2 (showed in Figure 3c).…”

“…In detail, during the mechanistic process, CD36‐induced is necessary for activation of ERK1/2, which is unfortunately insufficient owing to an ERK‐DUSP4 negative feedback pathway that can exert a negative effect on ERK1/2 activation, whereas the subsequent AC engulfment and phagolysosomal degradation could metabolize methionine to produce S‐adenosylmethionine (SAM) that could be used to induce DUSP4 methylation mediated by DNA methyltransferase‐3A (DNMT3A), leading to reduced DUSP4 and the enhancement of activation of ERK1/2 and the subsequent Ptgs2/COX2/PGE2/TGF‐β pathway. Then, PGE2 promotes the production of TGF‐β (Ampomah et al, 2022). Therefore, TGF‐β production is another outcome of metabolic load from ACs during efferocytosis (showed in Figure 3c).…”

Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis

“…PPARγ has long been recognized as a potential receptor for PUFA produced eicosanoids ( 170 ). These effects of PUFAs on CD36 expression and the function of macrophages to produce inflammatory metabolites are at least partially mediated through the activation of PPARs by the bioactive eicosanoids produced from PUFAs ( 171 – 173 ). In fact, cyclooxygenase 2 (COX-2), one of the enzymes metabolizing PUFAs to eicosanoids is only expressed in tissue and infiltrating macrophages in the healthy liver ( 174 ).…”

RAC-king up Efferocytosis in Atherosclerotic Plaques With Aldehyde Dehydrogenase 2 Deficiency

“…[7][8][9] If efferocytosis is efficient, this not only prevents postapoptotic necrosis, and concomitant proinflammatory triggers, but also contributes to resolution of existing inflammation. 10 In atherosclerosis, several molecular pathways explaining the observed defect in efferocytosis are already known, involving a.o. cleavage of receptors responsible for uptake of apoptotic cells, such as MFEG8 (milk-fat globulin e8), 11 MER Proto-Oncogene, Tyrosine Kinase (MerTK), 12,13 and LRP1 (low-density lipoprotein receptor related protein 1), and the dysregulation of eat-me ligands stimulating uptake, such as CD47.…”