Fueling defense: PPARα enhances macrophage inflammatory responses
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Peroxisome proliferator-activated receptor alpha is an essential factor in enhanced macrophage immune function induced by angiotensin-converting enzyme
Increased expression of angiotensin-converting enzyme (ACE) by myeloid lineage cells strongly increases the immune activity of these cells, as observed in ACE10/10 mice, which exhibit a marked increase in antitumor and antibactericidal immunity. We report that peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that regulates genes critical for lipid metabolism, is a key molecule in the enhanced macrophage function induced by ACE. Here, we used a Cre–LoxP approach with LysM-Cre to create a modified ACE10/10 mouse line in which macrophages continue to generate abundant ACE but in which monocyte and macrophage PPARα expression is selectively suppressed. These mice, termed A10-PPARα-Cre, have significantly increased growth of B16-F10 tumors compared with ACE10/10 mice with Cre expression. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-expressing macrophages, resulting in reduced tumor antigen-specific CD8+ T-cell generation. Additionally, the elevated bactericidal resistance typical of ACE10/10 mice was significantly reduced in A10-PPARα-Cre mice, such that these mice resembled WT mice in their resistance to methicillin-resistant Staphylococcus aureus (MRSA) infection. THP-1 cells expressing increased ACE (termed THP-1-ACE) constitute a human macrophage model with increased PPARα that shows enhanced cytotoxicity against tumor cells and better phagocytosis and killing of MRSA. RNA silencing of PPARα in THP-1-ACE cells reduced both tumor cell death and bacterial phagocytosis and clearance. In contrast, the in vivo administration of pemafibrate, a specific agonist of PPARα, to WT and A10-PPARα-Cre mice reduced B16-F10 tumor growth by 24.5% and 25.8%, respectively, but pemafibrate reduced tumors by 57.8% in ACE10/10 mice. With pemafibrate, the number of antitumor CD8+ T cells was significantly lower in A10-PPARα-Cre mice than in ACE10/10 mice. We conclude that PPARα is important in the immune system of myeloid cells, including wild-type cells, and that its increased expression by ACE-expressing macrophages in ACE10/10 mice is indispensable for ACE-dependent functional upregulation of macrophages in both mice and human cells.
Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets
Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.
LncRNA Gm35585 transcriptionally activates the peroxidase EHHADH against diet-induced fatty liver
Metabolic-dysfunction-associated steatotic liver disease is one of the most common chronic liver diseases worldwide and has no approved treatment thus far. Here we report that the hepatic overexpression of Gm35585, a novel lncRNA downregulated in the livers of mice fed a high-fat diet, is functionally important in alleviating hepatic lipid accumulation pathologies. Gm35585 activates the peroxisome proliferator-activated receptor α (PPARα) signaling pathway and promotes the expression of downstream PPARα-target gene, enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), which is one of the four enzymes of the peroxisomal β-oxidation pathway. Activation of EHHADH promotes the oxidation of long-chain fatty acids (LCFAs), and the increased levels of hepatic LCFAs contribute to metabolic-dysfunction-associated steatotic liver disease. Mechanistically, Gm35585 binds to retinoid X receptor α (RXRα) and then forms a PPARα/RXRα heterodimer with PPARα and guides the heterodimer to recognize the promoter of EHHADH, which is called peroxisome proliferator-activated receptor response element, causing transcriptional activation of EHHADH. Taken together, Gm35585 is a hepatic lipid metabolism regulator that activates EHHADH transcription, promoting peroxisomal β-oxidation of LCFAs and ultimately ameliorating diet-induced fatty liver.
A decrease in Flavonifractor plautii and its product, phytosphingosine, predisposes individuals with phlegm-dampness constitution to metabolic disorders
According to traditional Chinese medicine (TCM) constitutional theory, individuals with phlegm-dampness constitution (PDC) are at increased risk for metabolic disorders. Previous studies have indicated that PDC individuals exhibit gene expression changes associated with metabolic disorders, even individuals with normal metabolic indices. However, the biological mechanisms underlying these changes remain unclear. The gut microbiota has recently emerged as a promising avenue for elucidating TCM principles. Here, we revealed that individuals with PDC have distinct gut microbiota and serum metabolite profiles. A decrease in phytosphingosine was associated with increased PDC scores and metabolic disorder severity. Subsequent experiments demonstrated that Flavonifractor plautii can biosynthesize phytosphingosine, which was also negatively correlated with the PDC score. Interestingly, both F. plautii and phytosphingosine levels decreased in PDC subjects with normal metabolic indices. Fecal transplantation from these individuals accelerated the development of metabolic disorders in mice. However, supplementation with F. plautii and phytosphingosine ameliorated metabolic disorders by increasing phytosphingosine levels in the gut‒hepatic axis. Mechanistic investigations confirmed that phytosphingosine can directly bind to hepatic peroxisome proliferator-activated receptor α (PPARα) and activate its nuclear transcription activity, thereby regulating downstream gene expression related to glucose‒lipid metabolism. Our research indicates that the decrease in F. plautii and its product, phytosphingosine, contributes to gene expression changes related to metabolic disorders in PDC individuals and increases their susceptibility to metabolic disorders. These findings suggest that diagnosing PDC may be beneficial for identifying at-risk populations among apparently healthy individuals, thereby advancing the broader field of metabolic disorder prevention and TCM integration.
Role of macrophage in intervertebral disc degeneration
Intervertebral disc degeneration is a degenerative disease where inflammation and immune responses play significant roles. Macrophages, as key immune cells, critically regulate inflammation through polarization into different phenotypes. In recent years, the role of macrophages in inflammation-related degenerative diseases, such as intervertebral disc degeneration, has been increasingly recognized. Macrophages construct the inflammatory microenvironment of the intervertebral disc and are involved in regulating intervertebral disc cell activities, extracellular matrix metabolism, intervertebral disc vascularization, and innervation, profoundly influencing the progression of disc degeneration. To gain a deeper understanding of the inflammatory microenvironment of intervertebral disc degeneration, this review will summarize the role of macrophages in the pathological process of intervertebral disc degeneration, analyze the regulatory mechanisms involving macrophages, and review therapeutic strategies targeting macrophage modulation for the treatment of intervertebral disc degeneration. These insights will be valuable for the treatment and research directions of intervertebral disc degeneration.
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