Resolution of inflammation via RvD1/FPR2 signaling mitigates Nox2 activation and ferroptosis of macrophages in experimental abdominal aortic aneurysms

Abstract

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. Resolvin D1 (RvD1) is derived from ω-3 polyunsaturated fatty acids and is involved in the resolution phase of chronic inflammatory diseases. The aim of this study was to decipher the protective role of RvD1 via formyl peptide receptor 2 (FPR2) receptor signaling in attenuating abdominal aortic aneurysms (AAA). The elastase-treatment model of AAA in C57BL/6 (WT) mice and human AAA tissue was used to confirm our hypotheses. Elastase-treated FPR2 −/− mice had a significant increase in aortic diameter, proinflammatory cytokine production, immune cell infiltration (macrophages and neutrophils), elastic fiber disruption, and decrease in smooth muscle cell αactin expression compared to elastase-treated WT mice. RvD1 treatment attenuated AAA formation, aortic inflammation, and vascular remodeling in WT mice, but not in FPR2 −/− mice. Importantly, human AAA tissue demonstrated significantly decreased FPR2 mRNA expression compared to non-aneurysm human aortas. Mechanistically, RvD1/FPR2 signaling mitigated p47 phox phosphorylation and prevented hallmarks of ferroptosis, such as lipid peroxidation and Nrf2 translocation, thereby attenuating HMGB1 secretion. Collectively, this study demonstrates RvD1-mediated immunomodulation of FPR2 signaling on macrophages to mitigate ferroptosis and HMGB1 release, leading to resolution of aortic inflammation and remodeling during AAA pathogenesis.

Resolvin D1/N-formyl peptide receptor 2 ameliorates paclitaxel-induced neuropathic pain through the activation of IL-10/Nrf2/HO-1 pathway in mice

“…RvD1 is the endogenous agonist of formyl peptide receptor 2 (FPR2) ( 21 ). It has been shown that activation of FPR2 by RvD1 can exert anti-inflammatory effects in many diseases ( 22 , 23 ). As shown in Figure 7A , the FPR2 expression in BMDMs had no significant change after PTX treatment only.…”

Macrophage erythrophagocytosis and iron‐handling in the resolution of inflammation

“…Senescent erythrocytes may however also accumulate at sites of hemorrhagic inflammation, making erythrophagocytosis by macrophages and structural tissue cells 4 a crucial part of the resolution of inflammation towards tissue homeostasis. In particular, erytrophagocytosis and iron metabolism in structural cells in the cardiovascular system is part of the resolution of inflammation associated with intra‐plaque hemorrhages in atherosclerotic lesions, 4 valve leaflet hemorrhages in calcific aortic valve stenosis, 5 and inflammatory reactions in aortic aneurysms 6 …”

“…The resulting accumulation of intracellular iron may act as an inducer of cytotoxic ferroptosis. SPM may however prevent iron toxicity to macrophages through the mitigation of ferroptosis (Figure 1), which has been demonstrated in aortic inflammation and aneurysm formation 6 …”

“…In particular, erytrophagocytosis and iron metabolism in structural cells in the cardiovascular system is part of the resolution of inflammation associated with intra-plaque hemorrhages in atherosclerotic lesions, 4 valve leaflet hemorrhages in calcific aortic valve stenosis, 5 and inflammatory reactions in aortic aneurysms. 6 Accumulation of heme, as a consequence of erythrophagocytosis, is metabolized by heme-oxygenases (HO; Figure 1), of which HO-1 is an inducible enzyme that catalyzes the degradation of free heme into ferrous iron, biliverdin/bilirubin, and carbon monoxide (CO), the latter potentially directly contributing to the resolution phase. 7 HO-1 is upregulated during M2 macrophage polarization by IL-4, 8 indicating that the increased erythrophagocytosis reported in the article in this journal issue 3 is accompanied by increased macrophage capacity to handle the heme burden.…”

“…SPM may however prevent iron toxicity to macrophages through the mitigation of ferroptosis (Figure 1), which has been demonstrated in aortic inflammation and aneurysm formation. 6 Intracellular iron accumulation will typically flip the redox balance towards increased formation of reactive oxygene species (ROS).…”