Fibroblast growth factor signaling in macrophage polarization: impact on health and diseases.

Fibroblast growth factors (FGFs) are a versatile family of peptide growth factors that are involved in various biological functions, including cell growth and differentiation, embryonic development, angiogenesis, and metabolism. Abnormal FGF/FGF receptor (FGFR) signaling has been implicated in the pathogenesis of multiple diseases such as cancer, metabolic diseases, and inflammatory diseases. It is worth noting that macrophage polarization, which involves distinct functional phenotypes, plays a crucial role in tissue repair, homeostasis maintenance, and immune responses. Recent evidence suggests that FGF/FGFR signaling closely participates in the polarization of macrophages, indicating that they could be potential targets for therapeutic manipulation of diseases associated with dysfunctional macrophages. In this article, we provide an overview of the structure, function, and downstream regulatory pathways of FGFs, as well as crosstalk between FGF signaling and macrophage polarization. Additionally, we summarize the potential application of harnessing FGF signaling to modulate macrophage polarization.

The anti-inflammatory role of zDHHC23 through the promotion of macrophage M2 polarization and macrophage necroptosis in large yellow croaker (Larimichthys crocea).

Zinc finger Asp-His-His-Cys motif-containing (zDHHC) proteins, known for their palmitoyltransferase (PAT) activity, play crucial roles in diverse cellular processes, including immune regulation. However, their non-palmitoyltransferase immunomodulatory functions and involvement in teleost immune responses remain underexplored. In this study, we systematically characterized the zDHHC family in the large yellow croaker (Larimichthys crocea), identifying 22 members. Phylogenetic analysis unveiled that each of the 22 LczDHHCs formed distinct clusters with their orthologues from other teleost species. Furthermore, all LczDHHCs exhibited a highly conserved DHHC domain, as confirmed by tertiary structure prediction. Notably, LczDHHC23 exhibited the most pronounced upregulation following Pseudomonas plecoglossicida (P. plecoglossicida) infection of macrophage/monocyte cells (MO/MΦ). Silencing LczDHHC23 led to heightened pro-inflammatory cytokine expression and diminished anti-inflammatory cytokine levels in MO/MΦ during infection, indicating its anti-inflammatory role. Functionally, LczDHHC23 facilitated M2-type macrophage polarization, as evidenced by a significant skewing of MO/MΦ towards the pro-inflammatory M1 phenotype upon LczDHHC23 knockdown, along with the inhibition of MO/MΦ necroptosis induced by P. plecoglossicida infection. These findings highlight the non-PAT immunomodulatory function of LczDHHC23 in teleost immune regulation, broadening our understanding of zDHHC proteins in host-pathogen interactions, suggesting LczDHHC23 as a potential therapeutic target for immune modulation in aquatic species.

The Pivotal Role of Macrophages in the Pathogenesis of Pancreatic Diseases.

The pancreas is an organ with both exocrine and endocrine functions, comprising a highly organized and complex tissue microenvironment composed of diverse cellular and non-cellular components. The impairment of microenvironmental homeostasis, mediated by the dysregulation of cell-to-cell crosstalk, can lead to pancreatic diseases such as pancreatitis, diabetes, and pancreatic cancer. Macrophages, key immune effector cells, can dynamically modulate their polarization status between pro-inflammatory (M1) and anti-inflammatory (M2) modes, critically influencing the homeostasis of the pancreatic microenvironment and thus playing a pivotal role in the pathogenesis of the pancreatic disease. This review aims to summarize current findings and provide detailed mechanistic insights into how alterations mediated by macrophage polarization contribute to the pathogenesis of pancreatic disorders. By analyzing current research comprehensively, this article endeavors to deepen our mechanistic understanding of regulatory molecules that affect macrophage polarity and the intricate crosstalk that regulates pancreatic function within the microenvironment, thereby facilitating the development of innovative therapeutic strategies that target perturbations in the pancreatic microenvironment.

Human milk oligosaccharides regulate human macrophage polarization and activation in response to Staphylococcus aureus.

Human milk oligosaccharides (HMOs) are present in high numbers in milk of lactating women. They are beneficial to gut health and the habitant microbiota, but less is known about their effect on cells from the immune system. In this study, we investigated the direct effect of three structurally different HMOs on human derived macrophages before challenge with Staphylococcus aureus (S. aureus). The study demonstrates that individual HMO structures potently affect the activation, differentiation and development of monocyte-derived macrophages in response to S. aureus. 6´-Sialyllactose (6'SL) had the most pronounced effect on the immune response against S. aureus, as illustrated by altered expression of macrophage surface markers, pointing towards an activated M1-like macrophage-phenotype. Similarly, 6'SL increased production of the pro-inflammatory cytokines TNF-α, IL-6, IL-8, IFN-γ and IL-1ß, when exposing cells to 6'SL in combination with S. aureus compared with S. aureus alone. Interestingly, macrophages treated with 6'SL exhibited an altered proliferation profile and increased the production of the classic M1 transcription factor NF-κB. The HMOs also enhanced macrophage phagocytosis and uptake of S. aureus. Importantly, the different HMOs did not notably affect macrophage activation and differentiation without S. aureus exposure. Together, these findings show that HMOs can potently augment the immune response against S. aureus, without causing inflammatory activation in the absence of S. aureus, suggesting that HMOs assist the immune system in targeting important pathogens during early infancy.

miR-34a promotes the immunosuppressive function of multiple myeloma-associated macrophages by dampening the TLR-9 signaling.

BACKGROUND: Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR-T) cell therapy. However, a portion of MM patients do not respond to CAR-T therapy, and the reasons for this lack of response remain unclear. The objective of this study was to investigate the impact of miR-34a on the immunosuppressive polarization of macrophages obtained from MM patients. METHODS: The levels of miR-34a and TLR9 (Toll-like receptor 9) were examined in macrophages obtained from both healthy individuals and patients with MM. ELISA was employed to investigate the cytokine profiles of the macrophage samples. Co-culture experiments were conducted to evaluate the immunomodulatory impact of MM-associated macrophages on CAR-T cells. RESULTS: There was an observed suppressed activation of macrophages and CD4+ T lymphocytes in the blood samples of MM patients. Overexpression of miR-34a in MM-associated macrophages dampened the TLR9 expression and impaired the inflammatory polarization. In both the co-culture system and an animal model, MM-associated macrophages suppressed the activity and tumoricidal effect of CAR-T cells in a miR-34a-dependent manner. CONCLUSION: The findings imply that targeting the macrophage miR-34a/TLR9 axis could potentially alleviate the immunosuppression associated with CAR-T therapy in MM patients.

Exosomes from adipose-derived stem cells regulate macrophage polarization and accelerate diabetic wound healing via the circ-Rps5/miR-124-3p axis.

BACKGROUND: Adipose-derived stem cells (ADSCs) hold promising application prospects in the treatment of diabetic wounds, although the underlying mechanisms of repair have not been fully elucidated. This research aimed to elucidate the mechanisms by which ADSCs promote wound healing. METHODS: Exosomes from ADSCs were isolated and circRps5 level was identified. To investigate the role of circRps5 in the regulation, exosomes from differently treated ADSCs were used. Different exosomes were injected into the edge of the wound in diabetic mice, and the effects on wound healing status, pathology, collagen, cytokines, and macrophage phenotype were assessed. Raw264.7 cells were co-treated with high glucose and exosomes, and then cell phenotype and autophagy were examined in vitro, followed by the evaluation of miR-124-3p's impact on cell phenotype. RESULTS: Exosomes from ADSCs were isolated and identified using nanoparticle tracking analysis and exosome markers. Overexpression of circRps5 accelerated wound healing, reduced inflammatory response, enhanced collagen production, and promoted the M2 transformation of macrophages. In high glucose-induced macrophages, its overexpression also inhibited excessive autophagy. When macrophages overexpressed miR-124-3p, the induction of the M2 phenotype was suppressed. Luciferase reporter assay proved the combination of circRps5 and miR-124-3p. CONCLUSION: This study identifies that circRps5 carried by ADSC-Exos promotes macrophage M2 polarization through miR-124-3p. These findings provide valuable insights into the mechanism of ADSC-Exos for treating refractory diabetic wounds, laying a solid theoretical groundwork for future clinical development.

Strategies to reprogram anti-inflammatory macrophages towards pro-inflammatory macrophages to support cancer immunotherapies.

Tumor-associated myeloid cells, including macrophages and myeloid-derived suppressor cells, can be highly prevalent in solid tumors and play a significant role in the development of the tumor. Therefore, myeloid cells are being considered potential targets for cancer immunotherapies. In this review, we focused on strategies aimed at targeting tumor-associated macrophages (TAMs). Most strategies were studied preclinically but we also included a limited number of clinical studies based on these strategies. We describe possible underlying mechanisms and discuss future challenges and prospects.

Activation of the cGAS-STING pathway by viral dsDNA leading to M1 polarization of macrophages mediates antiviral activity against hepatitis B virus.

BACKGROUND AND AIMS: Activation of the cGAS-STING pathway induces the production of type I interferons, initiating the antiviral immune response, which contributes to the clearance of pathogens. Previous studies have shown that STING agonists promote hepatitis B virus (HBV) clearance; however, few studies have investigated the effect of activating the cGAS-STING pathway in macrophages on HBV. METHODS: The polarization status of HBV particle-stimulated RAW264.7 macrophages was analyzed. After stimulation with HBV particles, the analysis focused on determining whether the DNA sensors in RAW264.7 macrophages recognized the viral double-stranded DNA (dsDNA) and evaluating the activation of the cGAS-STING pathway. Coculture of mouse macrophages and hepatocytes harboring HBV was used to study the antiviral activity of HBV-stimulated RAW264.7 macrophages. RESULTS: After stimulation with HBV particles, HBV relaxed circular DNA (rcDNA) was detected in RAW264.7 macrophages, and the protein expression of phospho-STING, phospho-TBK1, and phospho-IRF3 in the STING pathway was increased, as shown by Western blot analysis, which revealed that M1 polarization of macrophages was caused by increased expression of CD86. RT-PCR analyses revealed elevated expression of M1 macrophage polarization-associated cytokines such as TNFα, IL-1ß, iNOS, and IFNα/ß. In the coculture experiment, both HBsAg and HBeAg expression levels were significantly decreased in AML12-HBV1.3 cells cocultured with the supernatants of HBV-stimulated RAW264.7 macrophages. CONCLUSION: The results suggest that macrophages can endocytose HBV particles. Additionally, viral dsDNA can be recognized by DNA pattern recognition receptors, which in turn activate the cGAS-STING pathway, promoting the M1 polarization of macrophages, while no significant M2 polarization is observed. Macrophages stimulated with HBV particles exhibit enhanced antiviral activity against HBV.

Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy.

Total tumor clearance through immunotherapy is associated with a fully coordinated innate and adaptive immune response, but knowledge on the exact contribution of each immune cell subset is limited. We show that therapy-induced intratumoral CD8+ T cells recruited and skewed late-stage activated M1-like macrophages, which were critical for effective tumor control in two different murine models of cancer immunotherapy. The activated CD8+ T cells summon these macrophages into the tumor and their close vicinity via CCR5 signaling. Exposure of non-polarized macrophages to activated T cell supernatant and tumor lysate recapitulates the late-stage activated and tumoricidal phenotype in vitro. The transcriptomic signature of these macrophages is also detected in a similar macrophage population present in human tumors and coincides with clinical response to immune checkpoint inhibitors. The requirement of a functional co-operation between CD8+ T cells and effector macrophages for effective immunotherapy gives warning to combinations with broad macrophage-targeting strategies.

Extracellular matrix stiffness and tumor-associated macrophage polarization: new fields affecting immune exclusion.

In the malignant progression of tumors, there is deposition and cross-linking of collagen, as well as an increase in hyaluronic acid content, which can lead to an increase in extracellular matrix stiffness. Recent research evidence have shown that the extracellular matrix plays an important role in angiogenesis, cell proliferation, migration, immunosuppression, apoptosis, metabolism, and resistance to chemotherapeutic by the alterations toward both secretion and degradation. The clinical importance of tumor-associated macrophage is increasingly recognized, and macrophage polarization plays a central role in a series of tumor immune processes through internal signal cascade, thus regulating tumor progression. Immunotherapy has gradually become a reliable potential treatment strategy for conventional chemotherapy resistance and advanced cancer patients, but the presence of immune exclusion has become a major obstacle to treatment effectiveness, and the reasons for their resistance to these approaches remain uncertain. Currently, there is a lack of exact mechanism on the regulation of extracellular matrix stiffness and tumor-associated macrophage polarization on immune exclusion. An in-depth understanding of the relationship between extracellular matrix stiffness, tumor-associated macrophage polarization, and immune exclusion will help reveal new therapeutic targets and guide the development of clinical treatment methods for advanced cancer patients. This review summarized the different pathways and potential molecular mechanisms of extracellular matrix stiffness and tumor-associated macrophage polarization involved in immune exclusion and provided available strategies to address immune exclusion.

The role of M1/M2 macrophage polarization in primary Sjogren's syndrome.

BACKGROUND: The purpose of this study was to investigate the role of macrophage polarization in the pathogenesis of primary Sjogren's syndrome (pSS). METHODS: Peripheral venous blood samples were collected from 30 patients with pSS and 30 healthy controls. Minor salivary gland samples were abtainted from 10 of these patients and 10 non-pSS controls whose minor salivary gland didn't fulfill the classification criteria for pSS. Enzyme-linked immuno sorbent assay was used to examine the serum concentration of M1/M2 macrophage related cytokines (TNF-a, IL-6, IL-23, IL-4, IL-10 and TGF-ß). Flow cytometry was used to examine the numbers of CD86+ M1 macrophages and CD206+ M2 macrophages in peripheral blood mononuclear cells (PBMCs). Immunofluorescence was used to test the infiltration of macrophages in minor salivary glands. RESULTS: This study observed a significant increase in pSS patients both in the numbers of M1 macrophages in peripheral blood and serum levels of M1-related pro-inflammatory cytokines (IL-6, IL-23 and TNF-α). Conversely, M2 macrophages were downregulated in the peripheral blood of pSS patients. Similarly, in the minor salivary glands of pSS patients, the expression of M1 macrophages was increased, and that of M2 macrophages was decreased. Furthermore, a significantly positive correlation was found between the proportions of M1 macrophages in PBMCs and serum levels of IgG and RF. CONCLUSIONS: This study reveals the presence of an significant imbalance in M1/M2 macrophages in pSS patients. The M1 polarization of macrophages may play an central role in the pathogenesis of pSS.

Transcriptome analysis of long non-coding RNAs in Mycobacterium avium complex-infected macrophages.

Mycobacterium avium complex (MAC) is a non-tuberculous mycobacterium widely distributed in the environment. Even though MAC infection is increasing in older women and immunocompromised patients, to our knowledge there has been no comprehensive analysis of the MAC-infected host-cell transcriptome-and particularly of long non-coding RNAs (lncRNAs). By using in vitro-cultured primary mouse bone-marrow-derived macrophages (BMDMs) and Cap analysis of gene expression, we analyzed the transcriptional and kinetic landscape of macrophage genes, with a focus on lncRNAs, during MAC infection. MAC infection of macrophages induced the expression of immune/inflammatory response genes and other genes similar to those involved in M1 macrophage activation, consistent with previous reports, although Nos2 (M1 activation) and Arg1 (M2 activation) had distinct expression profiles. We identified 31 upregulated and 30 downregulated lncRNA promoters corresponding respectively to 18 and 26 lncRNAs. Upregulated lncRNAs were clustered into two groups-early and late upregulated-predicted to be associated with immune activation and the immune response to infection, respectively. Furthermore, an Ingenuity Pathway Analysis revealed canonical pathways and upstream transcription regulators associated with differentially expressed lncRNAs. Several differentially expressed lncRNAs reported elsewhere underwent expressional changes upon M1 or M2 preactivation and subsequent MAC infection. Finally, we showed that expressional change of lncRNAs in MAC-infected BMDMs was mediated by toll-like receptor 2, although there may be other mechanisms that sense MAC infection. We identified differentially expressed lncRNAs in MAC-infected BMDMs, revealing diverse features that imply the distinct roles of these lncRNAs in MAC infection and macrophage polarization.

Tumor-derived extracellular vesicles regulate macrophage polarization: role and therapeutic perspectives.

Extracellular vesicles (EVs) are important cell-to-cell communication mediators. This paper focuses on the regulatory role of tumor-derived EVs on macrophages. It aims to investigate the causes of tumor progression and therapeutic directions. Tumor-derived EVs can cause macrophages to shift to M1 or M2 phenotypes. This indicates they can alter the M1/M2 cell ratio and have pro-tumor and anti-inflammatory effects. This paper discusses several key points: first, the factors that stimulate macrophage polarization and the cytokines released as a result; second, an overview of EVs and the methods used to isolate them; third, how EVs from various cancer cell sources, such as hepatocellular carcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, and glioblastoma cell sources carcinoma, promote tumor development by inducing M2 polarization in macrophages; and fourth, how EVs from breast carcinoma, pancreatic carcinoma, lungs carcinoma, and glioblastoma cell sources carcinoma also contribute to tumor development by promoting M2 polarization in macrophages. Modified or sourced EVs from breast, pancreatic, and colorectal cancer can repolarize M2 to M1 macrophages. This exhibits anti-tumor activities and offers novel approaches for tumor treatment. Therefore, we discovered that macrophage polarization to either M1 or M2 phenotypes can regulate tumor development. This is based on the description of altering macrophage phenotypes by vesicle contents.

Macrophage polarization in rheumatoid arthritis: signaling pathways, metabolic reprogramming, and crosstalk with synovial fibroblasts.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Macrophages are key effector cells that play a central role in RA pathogenesis through their ability to polarize into distinct functional phenotypes. An imbalance favoring pro-inflammatory M1 macrophages over anti-inflammatory M2 macrophages disrupts immune homeostasis and exacerbates joint inflammation. Multiple signaling pathways, including Notch, JAK/STAT, NF-κb, and MAPK, regulate macrophage polarization towards the M1 phenotype in RA. Metabolic reprogramming also contributes to this process, with M1 macrophages prioritizing glycolysis while M2 macrophages utilize oxidative phosphorylation. Redressing this imbalance by modulating macrophage polarization and metabolic state represents a promising therapeutic strategy. Furthermore, complex bidirectional interactions exist between synovial macrophages and fibroblast-like synoviocytes (FLS), forming a self-perpetuating inflammatory loop. Macrophage-derived factors promote aggressive phenotypes in FLS, while FLS-secreted mediators contribute to aberrant macrophage activation. Elucidating the signaling networks governing macrophage polarization, metabolic adaptations, and crosstalk with FLS is crucial to developing targeted therapies that can restore immune homeostasis and mitigate joint pathology in RA.

Proinflammatory polarization strongly reduces human macrophage in vitro phagocytosis of tumor cells in response to CD47 blockade.

Antibody-based CD47 blockade aims to activate macrophage phagocytosis of tumor cells. However, macrophages possess a high degree of phenotype heterogeneity that likely influences phagocytic capacity. In murine models, proinflammatory (M1) activation increases macrophage phagocytosis of tumor cells, but in human models, results have been conflicting. Here, we investigated the effects of proinflammatory polarization on the phagocytic response of human monocyte-derived macrophages in an in vitro model. Using both flow cytometry-based and fluorescence live-cell imaging-based phagocytosis assays, we observed that mouse monoclonal anti-CD47 antibody (B6H12) induced monocyte-derived macrophage phagocytosis of cancer cells in vitro. Proinflammatory (M1) macrophage polarization with IFN-γ+LPS resulted in a severe reduction in phagocytic response to CD47 blockade. This reduction coincided with increased expression of the antiphagocytic membrane proteins LILRB1 and Siglec-10 but was not rescued by combination blockade of the corresponding ligands. However, matrix metalloproteinase inhibitors (TAPI-0 or GM6001) partly restored response to CD47 blockade in a dose-dependent manner. In summary, these data suggest that proinflammatory (M1) activation reduces phagocytic response to CD47 blockade in human monocyte-derived macrophages.

A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.

Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.

Macrophage polarization: an important role in inflammatory diseases.

Macrophages are crucial cells in the human body's innate immunity and are engaged in a variety of non-inflammatory reactions. Macrophages can develop into two kinds when stimulated by distinct internal environments: pro-inflammatory M1-like macrophages and anti-inflammatory M2-type macrophages. During inflammation, the two kinds of macrophages are activated alternatively, and maintaining a reasonably steady ratio is critical for maintaining homeostasis in vivo. M1 macrophages can induce inflammation, but M2 macrophages suppress it. The imbalance between the two kinds of macrophages will have a significant impact on the illness process. As a result, there are an increasing number of research being conducted on relieving or curing illnesses by altering the amount of macrophages. This review summarizes the role of macrophage polarization in various inflammatory diseases, including autoimmune diseases (RA, EAE, MS, AIH, IBD, CD), allergic diseases (allergic rhinitis, allergic dermatitis, allergic asthma), atherosclerosis, obesity and type 2 diabetes, metabolic homeostasis, and the compounds or drugs that have been discovered or applied to the treatment of these diseases by targeting macrophage polarization.

Myeloid A20 is critical for alternative macrophage polarization and type-2 immune-mediated helminth resistance.

Background: Protective immunity against intestinal helminths requires induction of robust type-2 immunity orchestrated by various cellular and soluble effectors which promote goblet cell hyperplasia, mucus production, epithelial proliferation, and smooth muscle contractions to expel worms and re-establish immune homeostasis. Conversely, defects in type-2 immunity result in ineffective helminth clearance, persistent infection, and inflammation. Macrophages are highly plastic cells that acquire an alternatively activated state during helminth infection, but they were previously shown to be dispensable for resistance to Trichuris muris infection. Methods: We use the in vivo mouse model A20myel-KO, characterized by the deletion of the potent anti-inflammatory factor A20 (TNFAIP3) specifically in the myeloid cells, the excessive type-1 cytokine production, and the development of spontaneous arthritis. We infect A20myel-KO mice with the gastrointestinal helminth Trichuris muris and we analyzed the innate and adaptive responses. We performed RNA sequencing on sorted myeloid cells to investigate the role of A20 on macrophage polarization and type-2 immunity. Moreover, we assess in A20myel-KO mice the pharmacological inhibition of type-1 cytokine pathways on helminth clearance and the infection with Salmonella typhimurium. Results: We show that proper macrophage polarization is essential for helminth clearance, and we identify A20 as an essential myeloid factor for the induction of type-2 immune responses against Trichuris muris. A20myel-KO mice are characterized by persistent Trichuris muris infection and intestinal inflammation. Myeloid A20 deficiency induces strong classical macrophage polarization which impedes anti-helminth type-2 immune activation; however, it promotes detrimental Th1/Th17 responses. Antibody-mediated neutralization of the type-1 cytokines IFN-γ, IL-18, and IL-12 prevents myeloid-orchestrated Th1 polarization and re-establishes type-2-mediated protective immunity against T. muris in A20myel-KO mice. In contrast, the strong Th1-biased immunity in A20myel-KO mice offers protection against Salmonella typhimurium infection. Conclusions: We hereby identify A20 as a critical myeloid factor for correct macrophage polarization and appropriate adaptive mucosal immunity in response to helminth and enteric bacterial infection.

Puerarin Alleviates Experimental Autoimmune Thyroiditis by Regulating Macrophages.

Hashimoto's thyroiditis (HT) is the most common organ-specific autoimmune disease, predominantly affecting women. Although the pathogenesis of HT is incompletely understood, some studies have found that macrophage polarization plays a role. Puerarin is a soy isoflavone compound that has anti-inflammatory and immunomodulatory effects and regulates macrophage immune activity. This study aimed to verify the therapeutic effect of puerarin on HT and explored its regulatory effect on macrophage polarization imbalance in HT. Through bioinformatics analysis and molecular biology methods, it was found that macrophages increased significantly in HT patients and model mice. Immunological staining showed that puerarin intervention could reduce tissue inflammatory cell infiltration. Molecular biological examination displayed that puerarin could inhibit local and systemic inflammation levels, and the expression of marker thyroglobulin and thyroid peroxidase Abs. In vivo experimental results indicated that puerarin regulated macrophage polarity and reduced inflammatory damage, possibly by inhibiting the pyroptosis signaling pathway. In vivo macrophage clearance experiments demonstrated that puerarin relied on macrophages to exert its mechanism of action in treating HT. The results of this study indicate that macrophages are important mediators in the development of HT, and puerarin can regulate macrophage polarity and inflammatory status to provide thyroid tissue protection, which provides a new idea for the treatment of HT.

Metabolic reprogramming and macrophage polarization in granuloma formation.

This review article delves into the complexities of granuloma formation, focusing on the metabolic reprogramming within these immune structures, especially in tuberculosis and sarcoidosis. It underscores the role of the monocyte-macrophage lineage in granuloma formation and maintenance, emphasizing the adaptability of these cells to environmental cues and inflammatory stimuli. Key to the discussion is the macrophage polarization influenced by various cytokines, with a detailed exploration of the metabolic shifts towards glycolysis under hypoxic conditions and the utilization of the pentose phosphate pathway (PPP) for crucial biosynthetic processes. Significant attention is given to the metabolism of L-arginine in macrophages and its impact on immune response and granuloma function. The review also highlights the role of mechanistic target of rapamycin (mTOR) signaling in macrophage differentiation and its implications in granulomatous diseases. Discoveries such as elevated PPP activity in granuloma-associated macrophages and the protective role of NADPH against oxidative stress offer novel insights into granuloma biology. The review concludes by suggesting potential therapeutic targets within these metabolic pathways to modulate granuloma formation and function, proposing new treatment avenues for conditions characterized by chronic inflammation and granuloma formation. This work contributes significantly to the understanding of immune regulation and chronic inflammation, presenting avenues for future research and therapy in granulomatous diseases.