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Mono‐(2‐ethylhexyl) phthalate (MEHP) can accumulate in the liver and then lead to hepatic steatosis, while the underlying mechanism remains unclear. Inflammation plays an important role in the disorder of hepatic lipid metabolism. This study aims to clarify the role of the inflammatory response mediated by formyl peptide receptor 2 (FPR2) in steatosis of L02 cells exposed to MEHP. L02 cells were exposed to MEHP of different concentrations and different time. A steatosis model of L02 cells was induced with oleic acid and the cells were exposed to MEHP simultaneously. In addition, L02 cells were incubated with FPR2 antagonist and then exposed to MEHP. Lipid accumulation was determined by oil red O staining and extraction assay. The indicators related to lipid metabolism and inflammatory response were measured with appropriate kits. The relative expression levels of FPR2 and its ligand were determined by Western blot, and the interaction of them was detected by co‐immunoprecipitation. As a result, MEHP exposure could promote the occurrence and progression of steatosis and the secretion of chemokines and inflammatory factors in L02 cells. MEHP could also affect the expression and activation of FPR2 and the secretion of FPR2 ligands. In addition, the promotion effect of MEHP on the secretion of total cholesterol and interleukin 1β in L02 cells could be significantly inhibited by the FPR2 antagonist. We concluded that FPR2 might affect the promotion effect of MEHP on steatosis of L02 cells by mediating inflammatory response. [ABSTRACT FROM AUTHOR]

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 α‐actin 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 p47phox 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. [ABSTRACT FROM AUTHOR]

Background: Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) show persistent neuroinflammation, which promotes epileptogenesis and epilepsy progression, suggesting that endogenous resolution of inflammation is inadequate to relieve neuronal network hyperexcitability. To explore the potential roles of formyl peptide receptor 2 (FPR2), which is a key regulator of inflammation resolution, in epilepsy caused by FCDIIb and TSC, we examined the expression and cellular distribution of FPR2. Method: The expression of FPR2 and nuclear factor‐κB (NF‐κB) signaling pathway was examined by real‐time PCR, western blots, and analyzed via one‐way analysis of variance. The distribution of FPR2 was detected using immunostaining. The expression of resolvin D1 (RvD1, the endogenous ligand of FPR2) was observed via enzyme‐linked immunosorbent assay. Pearson's correlation test was used to evaluate the correlation between the expression levels of FPR2 and RvD1 and the clinical variants. Results: The expression of FPR2 was significantly lower in FCDIIb (p =.0146) and TSC (p =.0006) cortical lesions than in controls, as was the expression of RvD1 (FCDIIb: p =.00431; TSC: p =.0439). Weak FPR2 immunoreactivity was observed in dysmorphic neurons (DNs), balloon cells (BCs), and giant cells (GCs) in FCDIIb and TSC tissues. Moreover, FPR2 was mainly distributed in dysplastic neurons; it was sparse in microglia and nearly absent in astrocytes. The NF‐κB pathway was significantly activated in patients with FCDIIb and TSC, and the protein level of NF‐κB was negatively correlated with the protein level of FPR2 (FCDIIb: p =.00395; TSC: p =.0399). In addition, the protein level of FPR2 was negatively correlated with seizure frequency in FCDIIb (p =.0434) and TSC (p =.0351) patients. Conclusion: In summary, these results showed that the expression and specific distribution of FPR2 may be involved in epilepsy caused by FCDIIb and TSC, indicating that downregulation of FPR2 mediated the dysfunction of neuroinflammation resolution in FCDIIb and TSC. [ABSTRACT FROM AUTHOR]

Inositol hexaphosphate (IP6) is a dietary compound commonly obtained from corn, rice, etc. Although we may consume significant amount of IP6 daily, it is unclear whether this diet will impact macrophages' fate and function. Therefore, we characterized the underlying relationship between IP6 and macrophage polarization in this study. We specifically examined the signature gene expression profiles associated with pro‐ and anti‐inflammatory responses, and resolution of inflammation pathways in macrophages under the influence of IP6. Interestingly, our data suggested that IP6 polarizes bone marrow‐derived macrophages (BMDM) into an M2a‐like subtype. Our results also demonstrated that IP6 reduces lipopolysaccharide‐induced apoptosis and pro‐inflammatory responses in macrophages. In contrast, the expression levels of genes related to anti‐inflammatory responses and resolution of inflammation pathways are upregulated. Our findings collectively demonstrated that IP6 has profound modulation effects on macrophages, which warrant further research on the therapeutic benefits of IP6 for inflammatory diseases. [ABSTRACT FROM AUTHOR]

Chorioamnionitis (CAM), as a common intrauterine infectious disease, is the leading cause of premature birth, stillbirth, neonatal infection and sepsis. The formyl peptide receptor 2 (FPR2) is a member of GPCRs widely distributed in a variety of tissues and is associated with many inflammatory diseases. With the discovery of FPR2 in human placenta, the possibility of exploring the function of FPR2 in obstetrics is evolving. The Resolvin D1 (RvD1) plays an important role in the resolution of inflammation by combining with FPR2. In this study, we evaluated the role of FPR2 and RvD1 in CAM, not only in the human placenta but also in mouse models. The expression of FPR2 increased in the placenta of CAM patients and the downstream PPARγ/NF‐κB signalling changed accordingly. Moreover, Fpr2−/− mice were highly susceptible to LPS, displaying a worse CAM symptom, compared with WT mice. By establishing a model of trophoblast inflammation in vitro, it was confirmed that RvD1 rescued the effect of LPS on inflammation by combining with FPR2 and its downstream PPARγ/NF‐κB pathway. Otherwise, RvD1 improved the preterm labour in a mouse model of CAM induced by LPS. Altogether, these findings show that RvD1 alleviated the inflammation of trophoblast in vivo and in vitro through FPR2/PPARγ/NF‐κB pathway, suggesting RvD1/FPR2 might be a novel therapeutic strategy to alleviate CAM. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of the lipid mediator Resolvin D1 in experimental keratitis. C57BL/6J mice were injected with lipopolysaccharide (2 µg/eye), and after 24 hours, the corneal damage was assessed. Clinical score was quantified, and corneal inflammatory biomarkers were detected by immunohistochemistry. A robust accumulation of sub‐epithelial macrophages and polymorphonuclear leucocytes, chemokine (C‐X‐C motif) ligand 1 (also known as keratinocyte‐derived chemokine), interleukin‐10 and promoters of apoptosis was also observed in lipopolysaccharide‐treated mice. Formyl peptide receptor 2 corneal expression was also assessed. The corneal stroma treated with lipopolysaccharide was characterized by presence of macrophages of M1‐like subtype and immature fibroblastic cells, marked with Ki67, not fully differentiated in fibroblasts. Indeed, the staining of the cornea with anti‐vimentin antibodies, a marker of differentiated myofibroblasts, was very faint. Resolvin D1 attenuated all the inflammatory parameters assessed in the present study, except for IL‐10. In conclusion, the data presented here seem to be consistent with the hypothesis that Resolvin D1 protected the cornea from the lipopolysaccharide‐induced keratitis by acting on several inflammatory components of this damage, pivoted by Formyl peptide receptor 2 (FPR2) activation and macrophages‐leucocytes activity. [ABSTRACT FROM AUTHOR]

Many factors are involved in the process of nerve regeneration. Understanding the mechanisms regarding how these factors promote an efficient remyelination is crucial to deciphering the molecular and cellular processes required to promote nerve repair. Schwann cells (SCs) play a central role in the process of peripheral nerve repair/regeneration. Using a model of facial nerve crush injury and repair, we identified Annexin A1 (ANXA1) as the extracellular trigger of SC proliferation and migration. ANXA1 activated formyl peptide receptor 2 (FPR2) receptors and the downstream adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) signaling cascade, leading to SC proliferation and migration in vitro. SCs lacking FPR2 or AMPK displayed a defect in proliferation and migration. After facial nerve injury (FNI), ANXA1 promoted the proliferation of SCs and nerve regeneration in vivo. Collectively, these data identified the ANXA1/FPR2/AMPK axis as an important pathway in SC proliferation and migration. ANXA1‐induced remyelination and SC proliferation promotes FNI regeneration. [ABSTRACT FROM AUTHOR]

Aim The anti-inflammatory protein annexin A1 (AnxA1) and its formyl peptide receptor 2 ( FPR2) have protective effects in organ fibrosis. Their role in chronic kidney disease ( CKD) has not yet been elucidated. Our aim was to characterize the AnxA1/ FPR2 system in models of renal fibrosis. Methods Rats were treated with angiotensin receptor antagonist during the nephrogenic period ( ARAnp) to induce late-onset hypertensive nephropathy and fibrosis. Localization and regulation of AnxA1 and FPR2 were studied by quantitative real-time PCR and double labelling immunofluorescence. Biological effects of AnxA1 were studied in cultured renal fibroblasts from AnxA1−/− and wild-type mice. Results Angiotensin receptor antagonist during the nephrogenic period kidneys displayed matrix foci containing CD73+ fibroblasts, alpha-smooth muscle actin (a- SMA)+ myofibroblasts and CD68+ macrophages. TGF- β and AnxA1 mRNAs were ~threefold higher than in controls. AnxA1 was localized to macrophages and fibroblasts; myofibroblasts were negative. FPR2 was localized to fibroblasts, myofibroblasts, macrophages and endothelial cells. AnxA1 and FPR2 immunoreactive signals were increased in the foci, with fibroblasts and macrophages expressing both proteins. AnxA1−/− fibroblasts revealed higher α- SMA (sevenfold) and collagen 1A1 (Col1A1; 144-fold) mRNA levels than controls. Treatment of murine WT fibroblasts with TGF- β (22.5 ng mL 24 h−1) increased mRNA levels of α- SMA (9.3-fold) and Col1A1 (fourfold). These increases were greatly attenuated upon overexpression of AnxA1 (1.5- and 1.7-fold, respectively; P < 0.05). Human fibroblasts reacted similarly when receiving the FPR2 inhibitor WRW4. Conclusion Our results demonstrate that AnxA1 and FPR2 are abundantly expressed in the renal interstitium and modulate fibroblast phenotype and extracellular matrix synthesis activity. [ABSTRACT FROM AUTHOR]

Several aspects of HIV-1 virulence and pathogenesis are mediated by the envelope protein gp41. Additionally, peptides derived from the gp41 ectodomain have been shown to induce chemotaxis in monocytes and neutrophils. Whereas this chemotactic activity has been reported, it is not known how these peptides could be produced under biological conditions. The heptad repeat 1 ( HR1) region of gp41 is exposed to the extracellular environment and could therefore be susceptible to proteolytic processing into smaller peptides. Matriptase is a serine protease expressed at the surface of most epithelia, including the prostate and mucosal surfaces. Here, we present evidence that matriptase efficiently cleaves the HR1 portion of gp41 into a 22-residue chemotactic peptide MAT-1, the sequence of which is highly conserved across HIV-1 clades. We found that MAT-1 induced migration of primary neutrophils and monocytes, the latter of which act as a cellular reservoir of HIV during early stage infection. We then used formyl peptide receptor 1 ( FPR1) and FPR2 inhibitors, along with HEK 293 cells, to demonstrate that MAT-1 can induce chemotaxis specifically using FPR2, a receptor found on the surface of monocytes, macrophages and neutrophils. These findings are the first to identify a proteolytic cleavage product of gp41 with chemotactic activity and highlight a potential role for matriptase in HIV-1 transmission and infection at epithelial surfaces and within tissue reservoirs of HIV-1. [ABSTRACT FROM AUTHOR]