Modulate Macrophage Activation Research Articles

Fibrinogen-Like Protein 2 Protects the Aggravation of Hypertriglyceridemia on the Severity of Hypertriglyceridemia Acute Pancreatitis by Regulating Macrophages

Abstract Objective The mechanisms underlying the increased severity of hypertriglyceridemia acute pancreatitis (HTG-AP) remain poorly understood. Fibrinogen-like protein 2 (FGL2) has been identified as a regulator of macrophage activity, mediating immune suppression. This study aims to examine the role of FGL2 in the susceptibility to severe conditions of HTG-AP. Methods Both wild-type and FGL2 gene knockout C57BL/6 mice were utilized to establish HTG, AP, and HTG-AP models using P-407 and/or caerulein. Serum levels of triglycerides, total cholesterol, amylase, and lipase were assessed via biochemical analysis. Pancreatic and lung tissue injuries were evaluated using hematoxylin and eosin staining. Tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) levels in serum and pancreatic tissues were quantified using enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to assess the expression of FGL2, the macrophage marker CD68, and M1/M2 macrophage markers iNOS/CD163. Results The animal models were successfully established. Compared to wild-type mice, FGL2 knockout resulted in increased pathological injury scores in the pancreas and lungs, as well as elevated TNF-α, IL-1β, and IL-6 levels in serum and pancreatic tissue in the HTG group, with more pronounced effects observed in the HTG-AP group. The AP group alone did not exhibit significant changes due to FGL2 knockout. Further analysis revealed that FGL2 knockout increased CD68 expression but reduced CD163 expression in the pancreatic tissues in the HTG group. In the HTG-AP group, there was a marked increase in CD68 and iNOS expressions, coupled with a reduction in CD163 expression. Conclusion FGL2 knockout in HTG and HTG-AP mice resulted in increased inflammatory responses and a significant imbalance in M2 macrophages. These findings suggest that FGL2 plays a crucial role in mitigating the aggravation of HTG on the severity of HTG-AP by modulating macrophage activity.

8343 The Role Of Pancreatic Nerve Activity On The Development Of Beta Cell Dysfunction With The Macrophage-Beta Cell Interaction

Abstract Disclosure: J. Yu: None. Y. Wang: None. L. Sha: None. Islet inflammation is a vital factor to the beta cell dysfunction which is driven by inflammatory cytokines TNF-α and IL-1β released by resident macrophages. Pancreatic nerve innervates islet function and our previous study suggested that pancreatic nerve activity might involved in the development of pancreatic beta cell dysfunction. However, it is not known whether pancreatic nerve activity modulates macrophage activity and contributes to the macrophage - beta cell interaction. The aim of our study was to investigate the role of nerve activity on it and the possible mechanism. Methods: Sprague Dawley Rats and high fat diet-induced obese rates were used. An intrapancreatic nerve truck with its intact innervated pancreatic islets were used for the study. The nerve activity was evoked with electric nerve stimulation and insulin and ATP released by beta cells, TNF-α released by macrophages, and IL-1β released mainly by macrophages were measured with nerve activation. Results: Insulin secretion was induced significantly with the nerve activation (8 Hz). With nerve activation, ATP level was significantly increased by 25.5 ± 11.7%. The increased releases of insulin and ATP were abolished with cholinergic M receptor blocker atropine. With nerve activation, TNF-α and IL-1β levels were increased by 25.3±7.6% and 51.8±11.7%, respectively (p<0.05). Interestingly, the increases of TNF-α and IL-1β with nerve activation were also blocked by atropine. Since it is known that acetylcholine does not induce pro-inflammatory cytokine release in macrophages, we suspected that the nerve activity induced TNF-α and IL-1β releases were indirect. ATP is likely a candidate for the indirect effect as receptors. With applying Suramin, a ATP receptor blocker, nerve activation increased TNF-α release was inhibited significantly and IL-1β release was trended to inhibited. atropine, an M receptor blocker, compared with the Control group, decreased by 88.0±3.7% and 63.1±19.6%, respectively (p< 0.01). In obese rats, nerve activation increased TNF-α and IL-1β content by 68.1 ± 22.6% and 39.7 ± 7.4%, respectively, and suramin significantly inhibited the nerve activation induced increase of TNF-α release and trended to inhibit IL-1β release. Conclusion: Our results suggested that the pancreatic nerve activity contribute to the macrophage-beta cell interaction in the development of beta cells dysfunction by enhancing ATP release from islet beta cells. Presentation: 6/3/2024

Imperative role of adaptor proteins in macrophage toll-like receptor signaling pathways.

Macrophages are integral part of the body's defense against pathogens and serve as vital regulators of inflammation. Adaptor molecules, featuring diverse domains, intricately orchestrate the recruitment and transmission of inflammatory responses through signaling cascades. Key domains involved in macrophage polarization include Toll-like receptors (TLRs), Src Homology2 (SH2) and other small domains, alongside receptor tyrosine kinases, crucial for pathway activation. This review aims to elucidate the enigmatic role of macrophage adaptor molecules in modulating macrophage activation, emphasizing their diverse roles and potential therapeutic and investigative avenues for further exploration.

Pharmacological inhibition of N-Acylethanolamine acid amidase (NAAA) mitigates intestinal fibrosis through modulation of macrophage activity.

Intestinal fibrosis, a frequent complication of inflammatory bowel disease, is characterized by stricture formation with no pharmacological treatment to date. N-acylethanolamine acid amidase (NAAA) is responsible of acylethanolamides (AEs, e.g., palmitoylethanolamide and oleoylethanolamide) hydrolysis. Here, we investigated NAAA and AEs signalling in gut fibrosis. NAAA and AEs signalling were evaluated in human intestinal specimens from stenotic Crohn's diseases (CD) patients. Gut fibrosis was induced by TNBS, monitored by colonoscopy and unascertained by qRT-PCR, histological analyses, and confocal microscopy. Immune cells were analysed in mesenteric lymph nodes by FACS. Colonic fibroblasts were cultured in conditioned media derived from polarized or not bone marrow-derived macrophages (BMDM). IL-23 signalling was evaluated by qRT-PCR, ELISA, FACS, and western blot in BMDM and in lamina propria CX3CR1+ cells. In ileocolonic human CD strictures, increased transcript expression of NAAA was observed with a decrease of its substrates OEA and PEA. NAAA inhibition reduced intestinal fibrosis in vivo, as revealed by decrease in inflammatory parameters, collagen deposition and fibrosis genes, including epithelial to mesenchymal transition. More in-depth studies revealed modulation of the immune response related to IL-23 following NAAA inhibition. The antifibrotic actions of NAAA inhibition are mediated by Mφ and M2 macrophages that indirectly affect fibroblast collagenogenesis. NAAA inhibitor AM9053 normalized IL-23 signalling in BMDM and in lamina propria CX3CR1+ cells. Our findings provide new insights into the pathophysiological mechanism of intestinal fibrosis and identify NAAA as a promising target for the development of therapeutic treatments to alleviate CD fibrosis.

Macrophage-Centric Biomaterials for Bone Regeneration in Diabetes Mellitus: Contemporary Advancements, Challenges, and Future Trajectories.

Increased susceptibility to bone fragility and the diminution of bone regenerative capacity are recognized as significant and frequent sequelae of diabetes mellitus. Research has elucidated the pivotal role of macrophages in the pathogenesis and repair of diabetic bone defects. Notwithstanding this, the therapeutic efficacy of traditional interventions remains predominantly inadequate. Concomitant with substantial advancements in tissue engineering in recent epochs, there has been an escalation in the development of biomaterials designed to modulate macrophage activity, thereby augmenting osseous tissue regeneration in the context of hyperglycemia. This review amalgamates insights from extant research and delineates recent progressions in the domain of biomaterials that target macrophages for the regeneration of diabetic bone, whilst also addressing the clinical challenges and envisaging future directions within this field.

Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis

Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression of prototypical LXR targets and leads macrophages to a less inflammatory phenotype with a profibrotic gene signature. These studies underscore the role of LDs as reservoirs and metabolic hubs of bioactive lipids, and suggest that LDAH favorably modulates macrophage activation and protects against atherosclerosis via lipolytic mobilization of regulatory sterols.

Neutrophil-macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome.

Cytokine storm syndrome (CSS) is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies, infections, and autoimmune conditions. However, the potential interplay between innate immune cells is not fully understood. Here, using poly I:C and lipopolysaccharide (LPS)-induced cytokine storm models, a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model. Intravital imaging revealed neutrophil-derived extracellular vesicles (NDEVs) in the liver and spleen, which were captured by macrophages. NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models. Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite, itaconate, which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase (Acod1, encoded by Irg1). Irg1 in macrophages, but not in neutrophils, was critical for the NDEV-mediated anti-inflammatory effects. Mechanistically, NDEVs delivered miR-27a-3p, which suppressed the expression of Suclg1, the gene encoding the enzyme that metabolizes itaconate, thereby resulting in the accumulation of itaconate in macrophages. These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.

Functional transformation of macrophage mitochondria in cardiovascular diseases.

Mitochondria are pivotal in the modulation of macrophage activation, differentiation, and survival. Furthermore, macrophages are instrumental in the onset and progression of cardiovascular diseases. Hence, it is imperative to investigate the role of mitochondria within macrophages in the context of cardiovascular disease. In this review, we provide an updated description of the origin and classification of cardiac macrophages and also focused on the relationship between macrophages and mitochondria in cardiovascular diseases with respect to (1) proinflammatory or anti-inflammatory macrophages, (2) macrophage apoptosis, (3) macrophage pyroptosis, and (4) macrophage efferocytosis. Clarifying the relationship between mitochondria and macrophages can aid the exploration of novel therapeutic strategies for cardiovascular disease.

Macrophage colony-stimulating factor and its role in the tumor microenvironment: novel therapeutic avenues and mechanistic insights.

The tumor microenvironment is a complex ecosystem where various cellular and molecular interactions shape the course of cancer progression. Macrophage colony-stimulating factor (M-CSF) plays a pivotal role in this context. This study delves into the biological properties and functions of M-CSF in regulating tumor-associated macrophages (TAMs) and its role in modulating host immune responses. Through the specific binding to its receptor colony-stimulating factor 1 receptor (CSF-1R), M-CSF orchestrates a cascade of downstream signaling pathways to modulate macrophage activation, polarization, and proliferation. Furthermore, M-CSF extends its influence to other immune cell populations, including dendritic cells. Notably, the heightened expression of M-CSF within the tumor microenvironment is often associated with dismal patient prognoses. Therefore, a comprehensive investigation into the roles of M-CSF in tumor growth advances our comprehension of tumor development mechanisms and unveils promising novel strategies and approaches for cancer treatment.

In situ neutrophil apoptosis and macrophage efferocytosis mediated by Glycyrrhiza protein nanoparticles for acute inflammation therapy

In the progression of acute inflammation, the activation and recruitment of macrophages and neutrophils are mutually reinforcing, leading to amplified inflammatory response and severe tissue damage. Therefore, to regulate the axis of neutrophils and macrophages is essential to avoid tissue damage induced from acute inflammatory. Apoptotic neutrophils can regulate the anti-inflammatory activity of macrophages through the efferocytosis. The strategy of in situ targeting and inducing neutrophil apoptosis has the potential to modulate macrophage activity and transfer anti-inflammatory drugs. Herein, a natural glycyrrhiza protein nanoparticle loaded with dexamethasone (Dex@GNPs) was constructed, which could simultaneously regulate neutrophil and macrophage function during acute inflammation treatment by combining in situ neutrophil apoptosis and macrophage efferocytosis. Dex@GNPs can be rapidly and selectively internalized by neutrophils and subsequently induce neutrophils apoptosis through a ROS-dependent mechanism. The efferocytosis of apoptotic neutrophils not only promoted the polarization of macrophages into anti-inflammatory state, but also facilitated the transfer of Dex@GNPs to macrophages. This enabled dexamethasone to further modulate macrophage function. In mouse models of acute respiratory distress syndrome and sepsis, Dex@GNPs significantly ameliorated the disordered immune microenvironment and alleviated tissue injury. This study presents a novel strategy for drug delivery and inflammation regulation to effectively treat acute inflammatory diseases.

The role of macrophage polarization in tendon healing and therapeutic strategies: Insights from animal models.

Tendon injuries, a common musculoskeletal issue, usually result in adhesions to the surrounding tissue, that will impact functional recovery. Macrophages, particularly through their M1 and M2 polarizations, play a pivotal role in the inflammatory and healing phases of tendon repair. In this review, we explore the role of macrophage polarization in tendon healing, focusing on insights from animal models. The review delves into the complex interplay of macrophages in tendon pathology, detailing how various macrophage phenotypes contribute to both healing and adhesion formation. It also explores the potential of modulating macrophage activity to enhance tendon repair and minimize adhesions. With advancements in understanding macrophage behavior and the development of innovative biomaterials, this review highlights promising therapeutic strategies for tendon injuries.

Nanomaterial-based therapeutics for enhanced antifungal therapy.

The application of nanotechnology in antifungal therapy is gaining increasing attention. Current antifungal drugs have significant limitations, such as severe side effects, low bioavailability, and the rapid development of resistance. Nanotechnology offers an innovative solution to address these issues. This review discusses three key strategies of nanotechnology to enhance antifungal efficacy. Firstly, nanomaterials can enhance their interaction with fungal cells via ingenious surface tailoring of nanomaterials. Effective adhesion of nanoparticles to fungal cells can be achieved by electrostatic interaction or specific targeting to the fungal cell wall and cell membrane. Secondly, stimuli-responsive nanomaterials are developed to realize smart release of drugs in the specific microenvironment of pathological tissues, such as the fungal biofilm microenvironment and inflammatory microenvironment. Thirdly, nanomaterials can be designed to cross different physiological barriers, effectively addressing challenges posed by skin, corneal, and blood-brain barriers. Additionally, some new nanomaterial-based strategies in treating fungal infections are discussed, including the development of fungal vaccines, modulation of macrophage activity, phage therapy, the application of high-throughput screening in drug discovery, and so on. Despite the challenges faced in applying nanotechnology to antifungal therapy, its significant potential and innovation open new possibilities for future clinical antifungal applications.

Migration Inhibition Factor Secreted by Peripheral Blood Memory B Cells Binding to CD74-CD44 Receptor Complex Drives Macrophage Behavior in Alzheimer's Disease.

Dysregulation of the peripheral immune system is be involved in the neuroinflammation in Alzheimer disease (AD) and accelerate the disease progression. The contribution of immune cells, particularly B cells, to AD pathogenesis has gained attention in recent research. In this study, we investigated the role of Peripheral Blood Memory B cells (PBMBs) and their secreted Migration Inhibition Factor (MIF) in driving macrophage behavior in AD based on the scRNA-seq technique, immunofluorescence and flow cytometry. We discovered that MIF binds to the CD74-CD44 receptor complex on macrophages, influencing their behavior. The dysregulated macrophage response hampers the clearance of amyloid-beta (Aβ) plaques, exacerbating AD pathology. Targeting the MIF-CD74-CD44 signal pathway may hold therapeutic potential in modulating macrophage activity and mitigating neuroinflammation in AD. This study provides a further understanding of peripheral immune cells dysregulated in AD.

Exploration of ferroptosis and necroptosis-related genes and potential molecular mechanisms in psoriasis and atherosclerosis.

Ferroptosis and necroptosis are two recently identified forms of non-apoptotic cell death. Their dysregulation plays a critical role in the development and progression of Psoriasis (PsD) and Atherosclerosis (AS). This study explores shared Ferroptosis and necroptosis-related genes and elucidates their molecular mechanisms in PsD and AS through the analysis of public databases. Data sets for PsD (GSE30999) and AS (GSE28829) were retrieved from the GEO database. Differential gene expression (DEG) and weighted gene co-expression network analysis (WGCNA) were performed. Machine learning algorithms identified candidate biomarkers, whose diagnostic values were assessed using Receiver Operating Characteristic (ROC) curve analysis. Additionally, the expression levels of these biomarkers in cell models of AS and PsD were quantitatively measured using Western Blot (WB) and real-time quantitative PCR (RT-qPCR). Furthermore, CIBERSORT evaluated immune cell infiltration in PsD and AS tissues, highlighting the correlation between characteristic genes and immune cells. Predictive analysis for candidate drugs targeting characteristic genes was conducted using the DGIdb database, and an lncRNA-miRNA-mRNA network related to these genes was constructed. We identified 44 differentially expressed ferroptosis-related genes (DE-FRGs) and 30 differentially expressed necroptosis-related genes (DE-NRGs). GO and KEGG enrichment analyses revealed significant enrichment of these genes in immune-related and inflammatory pathways, especially in NOD-like receptor and TNF signaling pathways. Two ferroptosis-related genes (NAMPT, ZFP36) and eight necroptosis-related genes (C7, CARD6, CASP1, CTSD, HMOX1, NOD2, PYCARD, TNFRSF21) showed high sensitivity and specificity in ROC curve analysis. These findings were corroborated in external validation datasets and cell models. Immune infiltration analysis revealed increased levels of T cells gamma delta, Macrophages M0, and Macrophages M2 in PsD and AS samples. Additionally, we identified 43 drugs targeting 5 characteristic genes. Notably, the XIST-miR-93-5p-ZFP36/HMOX1 and NEAT1-miR-93-5p-ZFP36/HMOX1 pathways have been identified as promising RNA regulatory pathways in AS and PsD. The two ferroptosis-related genes (NAMPT, ZFP36) and eight necroptosis-related genes (C7, CARD6, CASP1, CTSD, HMOX1, NOD2, PYCARD, TNFRSF21) are potential key biomarkers for PsD and AS. These genes significantly influence the pathogenesis of PsD and AS by modulating macrophage activity, participating in immune regulation, and mediating inflammatory responses.

Sustained Release of Dexamethasone from 3D-Printed Scaffolds Modulates Macrophage Activation and Enhances Osteogenic Differentiation.

Enhancing osteogenesis via modulating immune cells is emerging as a new approach to address the current challenges in repairing bone defects and fractures. However, much remains unknown about the crosstalk between immune cells and osteolineage cells during bone formation. Moreover, biomaterial scaffold-based approaches to effectively modulate this crosstalk to favor bone healing are also lacking. This study is the first to investigate the interactions between macrophages and mesenchymal stem cells (MSCs) in co-cultures with the sustained release of an anti-inflammatory and pro-osteogenesis drug (dexamethasone) from three-dimensional (3D)-printed scaffolds. We successfully achieved the sustained release of dexamethasone from polycaprolactone (PCL) by adding the excipient-sucrose acetate isobutyrate (SAIB). Dexamethasone was released over 35 days in the 17-163 nM range. The osteogenic differentiation of MSCs was enhanced by M1 macrophages at early time points. The late-stage mineralization was dominated by dexamethasone, with little contribution from the macrophages. Besides confirming BMP-2 whose secretion was promoted by both dexamethasone and M1 macrophages as a soluble mediator for enhanced osteogenesis, IL-6 was found to be a possible new soluble factor that mediated osteogenesis in macrophage-MSC co-cultures. The phenotype switching from M1 to M2 was drastically enhanced by the scaffold-released dexamethasone but only marginally by the co-cultured MSCs. Our results offer new insight into macrophage-MSC crosstalk and demonstrate the potential of using drug-release scaffolds to both modulate inflammation and enhance bone regeneration.

Maggot debridement therapy stimulates wound healing by altering macrophage activation.

The purpose of this study is to determine the impact of maggot debridement therapy (MDT) on macrophages during the healing process of diabetic foot ulcers (DFU). The activation phenotype of macrophages during wound healing following MDT was evaluated using double staining immunohistochemistry (IHC). In addition, markers associated with macrophage activation were discovered using immunoblotting and real-time polymerase chain reaction (PCR). During the process of diabetic wound healing following MDT, the presence and over-expression of M2 macrophages were observed, while the under-expression of M1 macrophages was noted. In addition, the activation markers of macrophages exhibited a correlation with the indicated Th1/Th2 cytokines. MDT interventions have the potential to modulate macrophage activity, thereby aiding in the healing of diabetic foot wounds.

MyD88-dependent Toll-like receptor 2 signaling modulates macrophage activation on lysate-adsorbed Teflon™ AF surfaces in an in vitro biomaterial host response model.

The adsorbed protein layer on an implanted biomaterial surface is known to mediate downstream cell-material interactions that drive the host response. While the adsorption of plasma-derived proteins has been studied extensively, the adsorption of damage-associated molecular patterns (DAMPs) derived from damaged cells and matrix surrounding the implant remains poorly understood. Previously, our group developed a DAMP-adsorption model in which 3T3 fibroblast lysates were used as a complex source of cell-derived DAMPs and we demonstrated that biomaterials with adsorbed lysate potently activated RAW-Blue macrophages via Toll-like receptor 2 (TLR2). In the present study, we characterized the response of mouse bone marrow derived macrophages (BMDM) from wildtype (WT), TLR2-/- and MyD88-/- mice on Teflon™ AF surfaces pre-adsorbed with 10% plasma or lysate-spiked plasma (10% w/w total protein from 3T3 fibroblast lysate) for 24 hours. WT BMDM cultured on adsorbates derived from 10% lysate in plasma had significantly higher gene and protein expression of IL-1β, IL-6, TNF-α, IL-10, RANTES/CCL5 and CXCL1/KC, compared to 10% plasma-adsorbed surfaces. Furthermore, the upregulation of pro-inflammatory cytokine and chemokine expression in the 10% lysate in plasma condition was attenuated in TLR2-/- and MyD88-/- BMDM. Proteomic analysis of the adsorbed protein layers showed that even this relatively small addition of lysate-derived proteins within plasma (10% w/w) caused a significant change to the adsorbed protein profile. The 10% plasma condition had fibrinogen, albumin, apolipoproteins, complement, and fibronectin among the top 25 most abundant proteins. While proteins layers generated from 10% lysate in plasma retained fibrinogen and fibronectin among the top 25 proteins, there was a disproportionate increase in intracellular proteins, including histones, tubulins, actins, and vimentin. Furthermore, we identified 7 DAMPs or DAMP-related proteins enriched in the 10% plasma condition (fibrinogen, apolipoproteins), compared to 39 DAMPs enriched in the 10% lysate in plasma condition, including high mobility group box 1 and histones. Together, these findings indicate that DAMPs and other intracellular proteins readily adsorb to biomaterial surfaces in competition with plasma proteins, and that adsorbed DAMPs induce an inflammatory response in adherent macrophages that is mediated by the MyD88-dependent TLR2 signaling pathway.

Monitoring mRNA Expression Patterns in Macrophages in Response to Two Different Strains of Probiotics.

As an initial study to elucidate the molecular mechanism of how probiotics modulate macrophage activity, we monitored mRNA expression patterns in peritoneal macrophages (PMs) treated with two different strains of probiotics. After treatment with either Weissella cibaria WIKIM28 or Latilactobacillus sakei WIKIM50, total RNAs from PMs were isolated and subjected into gene chip analyses. As controls, mRNAs from vehicle (phosphate-buffered saline, PBS)-treated PMs were also subjected to gene chip analysis. Compared to vehicle (PBS)-treated PMs, WIKIM28-treated and WIKIM50-treated PMs exhibited a total of 889 and 432 differentially expressed genes with expression differences of at least 4 folds, respectively. Compared to WIKIM28-treated PMs, WIKIM50-treated PMs showed 25 up-regulated genes and 21 down-regulated genes with expression differences of more than 2 folds. Interestingly, mRNA transcripts of M2 macrophage polarization marker such as anxa1, mafb, and sepp1 were increased in WIKIM50-treated PMs comparing to those in WIKIM28-treated PMs. Reversely, mRNA transcripts of M1 macrophage polarization marker such as hdac9, ptgs2, and socs3 were decreased in WIKIM50-treated PMs comparing to those in WIKIM28-treated PMs. In agreement with these observations, mRNA expression levels of tumor necrosis factor-α and interleukin-1α were significantly reduced in WIKIM50-treated macrophages compared to those in WIKIM28-treated macrophages. These results may indicate that probiotics can be classified as two different types depending on their ability to convert macrophages into M1 or M2 polarization.

Modulation of Alveolar Macrophage Activity by Eugenol Attenuates Cigarette-Smoke-Induced Acute Lung Injury in Mice.

This study investigates the role of eugenol (EUG) on CS-induced acute lung injury (ALI) and how this compound is able to modulate macrophage activity. C57BL/6 mice were exposed to 12 cigarettes/day/5days and treated 15 min/day/5days with EUG. Rat alveolar macrophages (RAMs) were exposed to CSE (5%) and treated with EUG. In vivo, EUG reduced morphological changes inflammatory cells, oxidative stress markers, while, in vitro, it induced balance in the oxidative stress and reduced the pro-inflammatory cytokine release while increasing the anti-inflammatory one. These results suggest that eugenol reduced CS-induced ALI and acted as a modulator of macrophage activity.

Macrophage scavenger receptor A1 antagonizes abdominal aortic aneurysm via upregulating IRG1

AimsAbdominal aortic aneurysm (AAA) is a common, usually asymptomatic disease with high mortality and limited therapeutic options. Extensive extracellular matrix (ECM) fragmentation and transmural inflammation act as major pathological processes of AAA. However, the underlying regulatory mechanisms remain incompletely understood. Herein, we aimed to investigate the role of scavenger receptor A1 (SR-A1), a key pattern recognition receptor modulating macrophage activity, in pathogenesis of AAA. Methods and resultsThe AAA model was generated by administration of angiotensin II (Ang II) into apolipoprotein E knockout mice or peri-arterial application of calcium phosphate in C57BJ/6L mice. We found that SR-A1 was markedly down-regulated in the macrophages isolated from murine AAA aortas. Global or myeloid-specific ablation of SR-A1 aggravated vascular inflammation, loss of vascular smooth muscle cells and degradation of the extracellular matrix. These effects of SR-A1 deficiency on AAA development were mediated by suppressed immunoresponsive gene 1 (IRG1) and increased inflammatory response in macrophages. Mechanically, binding of SR-A1 with Lyn led to STAT3 phosphorylation and translocation into the nucleus, in which STAT3 promoted IRG1 transcription through directly binding to its promoter. Restoration of macrophage SR-A1 in SR-A1-deficient mice by bone marrow transplantation or administration of 4-octyl itaconate, the derivate of IRG1 product itaconate, could relieve murine AAA. ConclusionOur study reveals a protective effect of macrophage SR-A1–STAT3–IRG1 axis against aortic aneurysm formation via inhibiting inflammation.