Epidemiological evidence suggests that environmental pollutants precipitate the occurrence of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR), a receptor or sensor for various contaminants, is closely related to immunomodulation and the polarization of M2 macrophages. However, the mechanisms involving AhR and M2 macrophages in AR remain unclear.

Bioinformatics analysis of GEO datasets (GSE180697 and GSE180697) assessed AhR and IL4I1 expression levels, which were then verified in the nasal mucosa, monocytes and serum of patients with AR using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Primary human mononuclear cells were isolated from peripheral blood using a magnetic separation technique, and THP-1 cell lines with IL4I1 overexpression or downexpression were established through lentiviral constructs. M2 macrophages were induced with the cytokines CSF, IL4 and IL13 and then treated with the AhR agonist FICZ or inhibitor CH223191. The polarization of M2 macrophages was measured by flow cytometry and western blotting. Furthermore, primary nasal epithelial cells and macrophages were co-cultured to assess the epithelial-mesenchymal transition (EMT) in epithelial cells. The AR murine model was established using ovalbumin (OVA). Inflammation within the nasal mucosa and lung tissue was examined after CH223191 or IL4I1 treatment.

Nuclear translocation of AhR and upregulation of IL4I1 was observed in peripheral mononuclear cells and nasal mucosal tissue of patients with AR. Through the activation of AhR, IL4I1 promoted M2 macrophage polarization. Furthermore, modulation of the IL4I1/AhR axis regulated the migratory impact of OVA on T-M2 cells. The IL4I1/AhR axis was involved in the regulation of M2 macrophage-associated EMT and contributed to the expression of IL-33 and STAT6 phosphorylation in epithelial cells. In AR mice, increased AhR nuclear translocation and higher expression of IL4I1 and the M2 macrophage marker CD206 in the lungs was observed. The IL4I1/AhR axis exacerbated allergic symptoms in AR mice, fostering allergic inflammation within the nasal mucosa and lungs.

The IL4I1/AhR axis is activated within the mononuclear phagocyte system of patients with AR. This activation facilitates the polarization of mononuclear cells into M2 macrophages, which further aggravates EMT in epithelial cells and exacerbates inflammation in AR. This study may provide novel strategies for the precise treatment of AR.

We conducted a meta-analysis and Mendelian randomization study to analyze the association and causal relationship of genetic prediction between post-traumatic stress disorder and the risk of systemic lupus erythematosus.

A meta-analysis was conducted using hazard ratio, relative risk, odds ratio, and 95 % confidence intervals as effect measures. Summary data from genome-wide association studies on post-traumatic stress disorder and systemic lupus erythematosus were utilized to assess the causal relationship of genetic prediction between post-traumatic stress disorder and systemic lupus erythematosus using Mendelian randomization.

A meta-analysis showed that post-traumatic stress disorder was positively associated with the risk of systemic lupus erythematosus (RR = 1.85, 95 % CI = 1.61-2.12, p < 0.001). The results of Egger's test showed no publication bias (p = 0.823, p > 0.05). Sensitivity analysis showed that the meta-analysis results were stable (RR = 1.85, 95 % CI = 1.61-2.12). However, Mendelian Randomization analysis revealed no evidence of a causal relationship of genetic prediction between post-traumatic stress disorder and systemic lupus erythematosus (IVW OR: 1.001, 95 % CI: 0.805-1.245, p = 0.993).

There is a correlation between post-traumatic stress disorder and systemic lupus erythematosus, but Mendelian Randomization does not support a genetic causal effect of post-traumatic stress disorder on systemic lupus erythematosus. The potential causal relationship between the two factors may necessitate further in-depth research.

How IRF7 promotes autoimmune B cell responses and systemic autoimmunity is unclear. Analysis of spontaneous SLE-prone mice deficient in IRF7 uncovered the IRF7 role in regulating autoimmune germinal center (GC), plasma cell (PC) and autoantibody responses and disease. IRF7, however, was dispensable for foreign antigen driven GC, PC and antibody responses. Competitive bone marrow (BM) chimeras highlighted the importance of IRF7 in hematopoietic cells in spontaneous GC and PC differentiation. Single-cell-RNAseq of SLE-prone B cells indicated IRF7 mediated B cell differentiation through GC and PC fates. Mechanistic studies revealed that IRF7 promoted B cell differentiation through GC and PC fates by regulating the transcriptome, translation, and metabolism of SLE-prone B cells. Mixed BM chimeras demonstrated a requirement for B cell-intrinsic IRF7 in IgG autoantibody production but not sufficient for promoting spontaneous GC and PC responses. Altogether, we delineate previously unknown B cell-intrinsic and -extrinsic mechanisms of IRF7-promoted spontaneous GC and PC responses, loss of tolerance, autoantibody production and SLE development.

Chronic restraint stress (CRS) is a tumour-promoting factor. However, the underlying mechanism is unknown.

We aimed to investigate whether CRS promotes head and neck squamous cell carcinoma (HNSCC) by altering the oral microbiota and related metabolites and whether kynurenine (Kyn) promotes HNSCC by modulating CD8+ T cells.

4-nitroquinoline-1-oxide (4NQO)-treated mice were exposed to CRS. Germ-free mice treated with 4NQO received oral microbiota transplants from either CRS or control mouse donors. 16S rRNA gene sequencing and liquid chromatography-mass spectrometry were performed on mouse saliva, faecal and plasma samples to investigate alterations in their microbiota and metabolites. The effects of Kyn on HNSCC were studied using the 4NQO-induced HNSCC mouse model.

Mice subjected to CRS demonstrated a higher incidence of HNSCC and oral microbial dysbiosis than CRS-free control mice. Pseudomonas and Veillonella species were enriched while certain oral bacteria, including Corynebacterium and Staphylococcus species, were depleted with CRS exposure. Furthermore, CRS-altered oral microbiota promoted HNSCC formation, caused oral and gut barrier dysfunction, and induced a host metabolome shift with increased plasma Kyn in germ-free mice exposed to 4NQO treatment. Under stress conditions, we also found that Kyn activated aryl hydrocarbon receptor (AhR) nuclear translocation and deubiquitination in tumour-reactive CD8+ T cells, thereby promoting HNSCC tumourigenesis.

CRS-induced oral microbiota dysbiosis plays a protumourigenic role in HNSCC and can influence host metabolism. Mechanistically, under stress conditions, Kyn promotes CD8+ T cell exhaustion and HNSCC tumourigenesis through stabilising AhR by its deubiquitination.

Sepsis is a major cause of morbidity and mortality, but our understanding of the mechanisms underlying survival or susceptibility is limited. Here, as pathogens often subvert host defence mechanisms, we hypothesized that this might influence the outcome of sepsis. We used microbiota analysis, faecal microbiota transplantation, antibiotic treatment and caecal metabolite analysis to show that gut-microbiota-derived tryptophan metabolites including indoles increased host survival in a mouse model of Serratia marcescens sepsis. Infection in macrophage-specific aryl hydrocarbon receptor (AhR) knockout mice revealed that AhR activation induced transcriptional reprogramming in macrophages and increased bacterial clearance and host survival. However, culture supernatants from multiple bacterial pathogens inhibited AhR activation in vitro. We showed that the secreted siderophore, enterobactin, inhibited AhR activation in vitro and increased sepsis mortality in vivo. By contrast, oral or systemic tryptophan supplementation increased survival. These findings show that sepsis survival depends upon the interplay between pathogen inhibition and the activation of AhR by a microbiota-derived metabolite.

Developing strategies to improve the therapeutic efficacy of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in autoimmune diseases have garnered increased attention.

To evaluate whether rapamycin-induced autophagy within the systemic lupus erythematosus (SLE) inflammatory microenvironment (Rapa-SLE) augments the therapeutic effects of MSC-derived EVs in SLE.

The therapeutic potential of the resulting EVs (Rapa-SLE-EV) was assessed in MRL/lpr mice. Rapa-SLE-EVs were compared with EVs derived from MSCs from MSCs cultured with EV-depleted fetal bovine serum (FBS-EV), EVs from MSCs cultured with rapamycin-treated FBS (Rapa-FBS-EV), and EVs exposed to SLE serum without rapamycin (SLE-EV). The autoimmune response, renal function, and pathological damage were assessed among the mouse groups. Additionally, mechanistic investigations into the role of the anti-inflammatory protein IDO1 within the EVs.

Interaction with the SLE inflammatory microenvironment triggered autophagy in MSCs, which was further enhanced by rapamycin treatment. Rapa-SLE-EV administration significantly ameliorated the autoimmune response and renal damage in MRL/lpr mice, outperforming other MSC-EV groups. This treatment mitigated key manifestations of SLE, including reduced autoantibody levels, as well as splenomegaly, and lymphadenopathy. Furthermore, Rapa-SLE-EV demonstrated superior suppression of plasma inflammatory cytokines, preserved renal function, mitigated pathological damage, and reduced glomerular immune complex deposition. Mechanistically, Rapa-SLE-EV exhibits exceptional inhibitory effects on SLE-B cell function, benefited by the high expression of the anti-inflammatory protein IDO1, which was confirmed to enter SLE-B cells through EVs.

We developed a novel strategy to improve the therapeutic efficacy of MSC-EVs in SLE and confirmed that the immunomodulatory function of the MSC-EVs is enhanced through autophagic activation and interaction with the SLE serum microenvironment, a process likely benefited by the high expression of IDO1.

Ulcerative colitis (UC) is an intractable inflammatory bowel disease that threatens the health of patients. The limited availability of therapeutic strategies makes it imperative to explore more efficient and safer drugs. Indigo naturalis (IN) is a traditional Chinese medicine that possesses many pharmacological activities, including anti-inflammatory, antioxidant, and immunomodulatory activities. The treatment potential of IN for UC has been proven by numerous preclinical and clinical studies in recent years.

This article provides a comprehensive review of the utility and potential of IN in the treatment of UC.

'Indigo naturalis' 'Qing dai' 'Qingdai' 'Ulcerative colitis' and 'UC' are used as the keywords, and the relevant literature is collected from online databases (Elsevier, PubMed, and Web of Science).

Indirubin, indigo, isatin, tryptanthrin, and β-sitosterol are considered the key components in the treatment of UC with IN. Both preclinical and clinical studies support the efficacy of IN for UC, especially in severe UC or in those who do not respond to or have poor efficacy with existing therapies. The mechanisms of IN for UC are associated with the aryl hydrocarbon receptor pathway activation, immune regulation, oxidative stress inhibition, and intestinal microbial modulation. However, the clinical use of IN has the risks of adverse events such as pulmonary hypertension, which suggests the necessity for its rational application. As a potential therapeutic agent for UC that is currently receiving more attention, the clinical value of IN has been initially demonstrated and warrants further evaluation.

LN is a serious complication of systemic lupus erythematosus (SLE), affecting up to 60% of patients with SLE and may lead to end-stage renal disease (ESRD). Macrophages play multifaceted roles in the pathogenesis of LN, including clearance of immune complexes, antigen presentation, regulation of inflammation, and tissue repair. Macrophages are abundant in the glomeruli and tubulointerstitium of LN patients and are positively correlated with serum creatinine levels and the severity of renal pathology. It has been shown that the infiltration of macrophages is closely associated with several clinical indicators, such as serum creatinine and complement C3 levels, anti-dsDNA antibody titers, Austin score, interstitial fibrosis and renal tubular atrophy. Moreover, cytokines expressed by macrophages were upregulated at LN onset and downregulated after remission, suggesting that macrophages may serve as markers of LN pathogenesis and remission. Therapies targeting macrophages have been shown to alleviate LN. There are two main types of macrophages in the kidney: kidney-resident macrophages (KRMs) and monocyte-derived macrophages (MDMs). KRMs and MDMs play different pathological roles in LN, with KRMs promoting leukocyte recruitment at sites of inflammation by expressing monocyte chemokines, while MDMs may exacerbate autoimmune responses by presenting immune complex antigens. Macrophages exhibit high plasticity and can differentiate into various phenotypes in response to distinct environmental stimuli. M1 (proinflammatory) macrophages are linked to the progression of active SLE, whereas the M2 (anti-inflammatory) phenotype is observed during the remission phase of LN. The polarization of macrophages in LN can be manipulated through multiple pathways, such as the modulation of signaling cascades including TLR 2/1, S1P, ERS, metabolic reprogramming, and HMGB1. This paper provides a comprehensive overview of the role of macrophages in the progression of lupus nephritis (LN), and elucidates how these cells and their secretory products function as indicators and therapeutic targets for the disease in the context of diagnosis and treatment of LN.

Benzo(a)pyrene (BaP) is one of the most thoroughly studied polycyclic aromatic hydrocarbons(PAHs) and a widespread organic pollutant in various areas of human life. Its teratogenic, immunotoxic and carcinogenic effects on organisms are well documented and widely recognized by researchers. In the body, BaP is enzymatically converted to form a more active benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). BaP/BPDE has the potential to trigger gene mutations, influence epigenetic modifications and cause damage to cellular structures, ultimately contributing to disease onset and progression. However, there are different points of view when studying epigenetics using BaP/BPDE. On the one hand, it is claimed in cancer research that BaP/BPDE contributes to gene hypermethylation and, in particular, induces the hypermethylation of tumor's suppressor gene promoters, leading to gene silencing and subsequent cancer development. Conversely, studies in human and animal populations suggest that exposure to BaP results in genome-wide DNA hypomethylation, potentially leading to adverse outcomes in inflammatory diseases. This apparent contradiction has not been summarized in research for almost four decades. This article presents a comprehensive review of the current literature on the influence of BaP/BPDE on DNA methylation regulation. It demonstrates that BaP/BPDE exerts a dual-phase regulatory effect on methylation, which is influenced by factors such as the concentration and duration of BaP/BPDE exposure, experimental models and detection methods used in various studies. Acute/high concentration exposure to BaP/BPDE often results in global demethylation of DNA, which is associated with inhibition of DNA methyltransferase 1 (DNMT1) after exposure. At certain specific gene loci (e.g., RAR-β), BPDE can form DNA adducts, recruiting DNMT3 and leading to hypermethylation at specific sites. By integrating these different mechanisms, our goal is to unravel the patterns and regulations of BaP/BPDE-induced DNA methylation changes and provide insights into future precision therapies targeting epigenetics.

New approaches to treat autoimmune diseases are needed, and we can be inspired by mechanisms in immune tolerance to guide the design of these approaches. Efferocytosis, the process of phagocyte-mediated apoptotic cell (AC) disposal, represents a potent tolerogenic mechanism that we could draw inspiration from to restore immune tolerance to specific autoantigens. ACs engage multiple avenues of the immune response to redirect aberrant immune responses. Two such avenues are: phosphatidylserine on the outer leaflet of the cell and engaging the aryl hydrocarbon receptor (AhR) pathway. We incorporated these two avenues into one acetalated dextran (Ace-DEX) microparticle (MP) for evaluation in vitro. First phosphatidylserine (PS) was incorporated into Ace-DEX MPs and evaluated for cellular association and mediators of cell tolerance including IL-10 production and M2 associated gene expression when particles were cultured with peritoneal macrophages (PMacs). Further PS Ace-DEX MPs were evaluated as an agent to suppress LPS stimulated PMacs. Then, AhR agonist 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) was incorporated into Ace-DEX MPs and expression of M2 and IL-10 genes was evaluated in PMacs. Further the ITE and PS Ace-DEX MPs (PS/ITE MPs) were evaluated for suppression of T cell priming and Th1 polarization. Our results indicate that the PS/ITE-MPs stimulated anti-inflammatory cytokine expression and suppressed inflammation following LPS stimulation of PMacs. Moreover, PS/ITE MPs induced the anti-inflammatory enzyme IDO1 and suppressed macrophage-mediated T cell priming and Th1 polarization. These findings suggest that PS and ITE-loaded Ace-DEX MPs could be a promising therapeutic tool for suppressing inflammation.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor whose expression regulates immune cell differentiation. Single-cell transcriptomic profiling was used to ascertain the heterogeneity of AHR expression in human B cell subpopulations. We identified a unique population of B cells marked by expression of AHR, CD9, and myeloid genes such as CD14 and CXCL8. Results were confirmed directly in human PBMCs and purified B cells at the protein level. TLR9 signaling induced CD14, CD9, and IL-8 protein expression in CD19+ B cells. CD14-expressing CD9+ B cells also highly expressed AHR and atypical B cell markers such as CD11c and TBET. In patients with active lupus disease, CD14+ and CD9+ B cells are dysregulated, with loss of CD9+ B cells strongly predicting disease severity and demonstrating the relevance of CD9+ B cells in systemic lupus erythematosus and autoimmune disease.

Despite our increasing understanding of macrophage heterogeneity, drivers of macrophage phenotypic and functional polarization in the microenvironment are not fully elucidated. Here, our single-cell RNA sequencing data identify a subpopulation of macrophages expressing high levels of the phagocytic receptor MER proto-oncogene tyrosine kinase (MerTK+ macrophages), which is closely associated with melanoma progression and immunotherapy resistance. Adoptive transfer of the MerTK+ macrophages into recipient mice notably accelerated tumor growth regardless of macrophage depletion. Mechanistic studies further revealed that ALK And LTK Ligand 1 (ALKAL1), a target gene of aryl hydrocarbon receptor (AhR), facilitated MerTK phosphorylation, resulting in heightened phagocytic activity of MerTK+ macrophages and their subsequent polarization toward an immunosuppressive phenotype. Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti-programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK+ macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.

Background Serotonin (5-HT) is a neurotransmitter with extensive physiological influence in the central nervous system (CNS) and various behavioral and biological functions, including immune regulation through 5-HT receptors (5-HTRs) expressed by immune cells. A variety of serotonin-modulating drugs have been developed to treat neurological disorders. Phenelzine, a drug indicated for the management of treatment-resistant depression, is a potent, non-selective inhibitor of monoamine oxidase (MAO), the enzyme that metabolizes serotonin to 5-hydroxyindole acetic acid (5-HIAA). Given the emerging evidence of a bidirectional link between depression and inflammation, as well as the potential therapeutic applications of serotonin-modulating drugs in autoimmune diseases and cancer, our study investigated the pro-inflammatory and anti-inflammatory factors influenced by serotonin and phenelzine. Methodology We conducted experiments on RAW264.7 macrophages, exposing them to various combinations and concentrations of serotonin, 5-HIAA, and phenelzine. We assessed the relative gene expression of monoamine oxidase-A (MAO-A), CYP1B1, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) using real-time PCR and measured the production of IL-6, TNF-α, and IL-10 cytokines using enzyme-linked immunosorbent assays (ELISA). Results Our findings revealed that phenelzine can downregulate genes associated with the production of reactive oxygen and nitrogen species, reduce aryl hydrocarbon receptor (AHR)-related gene expression induced by serotonin, and enhance the production of inflammatory cytokines. These effects were significantly influenced by the concentration of available serotonin. Conclusions Our study demonstrates that various mechanisms, including AHR activation, modulation of reactive oxygen and nitrogen species production, and others, in addition to the increased availability of serotonin due to phenelzine treatment, can significantly influence the inflammatory state.

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), continues to pose a significant clinical and scientific challenge. The most significant finding of recent years is that PDAC tumours harbour their specific microbiome, which differs amongst tumour entities and is distinct from healthy tissue. This review aims to evaluate and summarise all PDAC studies that have used the next-generation technique, 16S rRNA gene amplicon sequencing within each bodily compartment. As well as establishing a causal relationship between PDAC and the microbiome.

This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. A comprehensive search strategy was designed, and 1727 studies were analysed.

In total, 38 studies were selected for qualitative analysis and summarised significant PDAC bacterial signatures. Despite the growing amount of data provided, we are not able to state a universal 16S rRNA gene microbial signature that can be used for PDAC screening. This is most certainly due to the heterogeneity of the presentation of results, lack of available datasets, and the intrinsic selection bias between studies.

Several key studies have begun to shed light on causality and the influence the microbiome constituents and their produced metabolites could play in tumorigenesis and influencing outcomes. The challenge in this field is to shape the available microbial data into targetable signatures. Making sequenced data readily available is critical, coupled with the coordinated standardisation of data and the need for consensus guidelines in studies investigating the microbiome in PDAC.

The aryl hydrocarbon receptor is a ligand dependent transcription factor which functions as an environmental sensor. Originally discovered as the sensor for man made pollutants such as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) it has recently gained prominence as an important mediator for environmental triggers via the diet or microbiota which influences many physiological functions in different cell types and tissues across the body. Notably AHR activity contributes to prevent excessive inflammation following tissue damage in barrier organs such as skin, lung or gut which has received wide attention in the past decade. In this review we will focus on emerging common AHR functions across cell types and tissues and discuss ongoing issues that confound the understanding of AHR physiology. Furthermore, we will discuss the need for deeper molecular understanding of the functional activity of AHR in different contexts with respect to development of potential therapeutic applications.

Autoimmune diseases represent a complex array of conditions where the body's immune system mistakenly attacks its own tissues. These disorders, affecting millions worldwide, encompass a broad spectrum of conditions ranging from rheumatoid arthritis and multiple sclerosis to lupus and type 1 diabetes. The Aryl hydrocarbon receptor (AhR) translocator, expressed across immune and other cell types, plays crucial roles in immune disorders and inflammatory diseases. With a realm towards natural remedies in modern medicine for disease prevention, this study investigates the electronic properties and behaviors of bioactive compounds from dietary sources, including Apium graveolens L. (Celery), Coriandrum sativum seeds (Coriander), and Mentha longifolia, as AhR modulators. Through comprehensive analysis (HOMO-LUMO, ESP, LOL, and ELF), electron-rich and -poor regions, electron localization, and delocalization are identified, contrasting these compounds with the toxic AhR ligand, TCDD. Evaluation of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties reveals favorable pharmacokinetics without blood-brain barrier penetration, indicating drug-like characteristics. Molecular docking demonstrates stronger interactions of dietary flavonoid ligands with AhR transcription compared to TCDD. Molecular dynamics simulations confirm the stability of complexes and the sustainability of interactions formed. This research underscores the potential of natural compounds as effective AhR modulators for therapeutic interventions in immune-related disorders.

Acinetobacter baumannii is a pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection. Pharmacological inhibition of FOS reduces the cytotoxicity of A. baumannii in cell-based models, and similar results are also observed in a mouse infection model. A. baumannii outer membrane vesicles (OMVs) are shown to activate the aryl hydrocarbon receptor (AHR) of host cells by inducing the host enzyme tryptophan-2,3-dioxygenase (TDO), producing the ligand kynurenine, which binds AHR. Following ligand binding, AHR is a direct transcriptional activator of the FOS gene. We propose that A. baumannii infection impacts the host tryptophan metabolism and promotes AHR- and FOS-mediated cytotoxicity of infected cells.

The maternal-fetal interface is composed of the placenta, which is affiliated with the fetus, and the maternal decidua. During pregnancy, the placenta is mainly responsible for nutrient transport and immune tolerance maintenance, which plays a key role in fetal growth and development and pregnancy maintenance. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that exists in various cell types at the maternal-fetal interface and is involved in multiple cellular processes. Recent studies have highlighted the role of AhR in regulating various physiological processes, including glucose and lipid metabolism, as well as tryptophan metabolism and immune responses, within non-pregnant tissues. This review shifts focus towards understanding how AhR modulation impacts metabolism and immune regulation at the maternal-fetal interface. This may implicate the development of pregnancy-related complications and the potential target of the AhR pathway for therapeutic strategies against poor pregnancy outcomes.

Primary Sjögren syndrome (pSS) is a chronic autoimmune disease mainly affecting salivary and lacrimal glands. The current pSS biomarkers, serum autoantibodies, are negative in many pSS patients diagnosed with histopathology changes, indicating the need of novel biomarkers. The current therapies of pSS are merely short-term symptomatic relief and can't provide effective long-term remedy. Extracellular vehicles (EVs) are nano-sized lipid bilayer-delimited particles spontaneously released by almost all types of cells and carrying various bioactive molecules to mediate inter-cellular communications. Recent studies found that EVs from salivary gland epithelial cells and immune cells play essential roles in pSS pathogenesis. Correspondingly, EVs and their cargos in plasma and saliva are promising candidate biomarkers for pSS diagnosis. Moreover, EVs from mesenchymal stem cells have shown promises to improve pSS treatment by modulating immune responses. This review summarizes recent findings in roles of EVs in pSS pathogenesis, diagnosis, and treatment of pSS, as well as related challenges and future research directions.

Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.

This review discusses the potential of targeting the kynurenine pathway (KP) in the treatment of inflammatory diseases. The KP, responsible for the catabolism of the amino acid tryptophan (TRP), produces metabolites that regulate various physiological processes, including inflammation, cell cycle, and neurotransmission. These metabolites, although necessary to maintain immune balance, may accumulate excessively during inflammation, leading to systemic disorders. Key KP enzymes such as indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), tryptophan 2,3-dioxygenase (TDO), and kynurenine 3-monooxygenase (KMO) have been considered promising therapeutic targets. It was highlighted that both inhibition and activation of these enzymes may be beneficial, depending on the specific inflammatory disorder. Several inflammatory conditions, including autoimmune diseases, for which modulation of KP activity holds therapeutic promise, have been described in detail. Preclinical studies suggest that this modulation may be an effective treatment strategy for diseases for which treatment options are currently limited. Taken together, this review highlights the importance of further research on the clinical application of KP enzyme modulation in the development of new therapeutic strategies for inflammatory diseases.

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.

Macrophages play an essential role in the innate immune system by differentiating into functionally diverse subsets in order to fight infection, repair damaged tissues, and regulate inappropriate immune responses. This functional diversity stems from their ability to adapt and respond to signals in the environment, which is in part mediated through aryl hydrocarbon receptor (AHR)-signaling. AHR, an environmental sensor, can be activated by various ligands, ranging from environmental contaminants to microbially derived tryptophan metabolites. This review discusses what is currently known about how AHR-signaling influences macrophage differentiation, polarization, and function. By discussing studies that are both consistent and divergent, our goal is to highlight the need for future research on the mechanisms by which AHR acts as an immunological switch in macrophages. Ultimately, understanding the contexts in which AHR-signaling promotes and/or inhibits differentiation, proinflammatory functions, and immunoregulatory functions, will help uncover functional predictions of immunotoxicity following exposure to environmental chemicals as well as better design AHR-targeted immunotherapies.

Persistent systemic chronic inflammatory conditions are linked with many pathologies, including cardiovascular diseases (CVDs), a leading cause of death across the globe. Among various risk factors, one of the new possible contributors to CVDs is the metabolism of essential amino acid tryptophan. Proinflammatory signals promote tryptophan metabolism via the kynurenine (KYN) pathway (KP), thereby resulting in the biosynthesis of several immunomodulatory metabolites whose biological effects are associated with the development of symptoms and progression of various inflammatory diseases. Some participants in the KP are agonists of aryl hydrocarbon receptor (AhR), a central player in a signaling pathway that, along with a regulatory influence on the metabolism of environmental xenobiotics, performs a key immunomodulatory function by triggering various cellular mechanisms with the participation of endogenous ligands to alleviate inflammation. An AhR ligand with moderate affinity is the central metabolite of the KP: KYN; one of the subsequent metabolites of KYN-kynurenic acid (KYNA)-is a more potent ligand of AhR. Understanding the role of AhR pathway-related metabolites of the KP that regulate inflammatory factors in cells of the cardiovascular system is interesting and important for achieving effective treatment of CVDs. The purpose of this review was to summarize the results of studies about the participation of the KP metabolite-KYNA-and of the AhR signaling pathway in the regulation of inflammation in pathological conditions of the heart and blood vessels and about the possible interaction of KYNA with AhR signaling in some CVDs.

Dysbiosis is emerging as a potential trigger of systemic lupus erythematosus (SLE). Group 3 innate lymphoid cells (ILC3s) are recognised as key regulators of intestinal homeostasis. The aryl hydrocarbon receptor (AhR) is critical to intestinal ILC3 development and function. This mechanistic review aimed to investigate whether AhR activation of gut ILC3s facilitates IL-22-mediated antimicrobial peptide (AMP) production to enhance colonisation resistance and ameliorate SLE pathology associated with intestinal dysbiosis. Furthermore, nutritional AhR ligand potential to enhance pathogen resistance was explored.

This mechanistic review involved a three-tranche systematic literature search (review, mechanism, intervention) using PubMed with critical appraisal. Data was synthesised into themes and summarised in a narrative analysis.

Preclinical mechanistic data indicate that AhR modulation of intestinal ILC3s optimises pathogen resistance via IL-22-derived AMPs. Pre-clinical research is required to validate this mechanism in SLE. Data on systemic immune consequences of AhR modulation in lupus suggest UVB-activated ligands induce aberrant AhR signalling while many dietary ligands exert beneficial effects. Data on xenobiotic-origin ligands is varied, although considerable evidence has demonstrated negative effects on Th17 to Treg balance. Limited human evidence supports the role of nutritional AhR ligands in modulating SLE pathology. Preclinical and clinical data support anti-inflammatory effects of dietary AhR ligands.

Current evidence is insufficient to fully validate the hypothesis that AhR modulation of intestinal ILC3s can enhance pathogen resistance to ameliorate lupus pathology driven by dysbiosis. However, anti-inflammatory effects of dietary AhR ligands suggest a promising role as a therapeutic intervention for SLE.

The interplay between myeloid cells and T-lymphocytes is critical to the regulation of host defense and inflammation resolution. Dysregulation of this interaction can contribute to the development of chronic inflammatory diseases. Important among these diseases is atherosclerosis, which refers to focal lesions in the arterial intima driven by elevated apolipoprotein B-containing lipoproteins, notably low-density lipoprotein (LDL), and characterized by the formation of a plaque composed of inflammatory immune cells, a collection of dead cells and lipids called the necrotic core, and a fibrous cap. As the disease progresses, the necrotic core expands, and the fibrous cap becomes thin, which increases the risk of plaque rupture or erosion. Plaque rupture leads to a rapid thrombotic response that can give rise to heart attack, stroke, or sudden death. With marked lowering of circulating LDL, however, plaques become more stable and cardiac risk is lowered-a process known as atherosclerosis regression. A critical aspect of both atherosclerosis progression and regression is the crosstalk between innate (myeloid cells) and adaptive (T-lymphocytes) immune cells. Myeloid cells are specialized at clearing apoptotic cells by a process called efferocytosis, which is necessary for inflammation resolution. In advanced disease, efferocytosis is impaired, leading to secondary necrosis of apoptotic cells, inflammation, and, most importantly, defective tissue resolution. In regression, efferocytosis is reawakened aiding in inflammation resolution and plaque stabilization. Here, we will explore how efferocytosing myeloid cells could affect T-cell function and vice versa through antigen presentation, secreted factors, and cell-cell contacts and how this cellular crosstalk may contribute to the progression or regression of atherosclerosis.

Subfertility remains a major problem in the dairy industry. Only 35-40% of high-yielding dairy cows and 55-65% of nonlactating heifers become pregnant after their first service. The immune system plays a critical role in the establishment of pregnancy. However, it can also create challenges for embryo survival and contribute to reduced fertility. We conducted 2 separate experiments to characterize changes in subsets of peripheral blood leukocytes (PBL) and their phenotype over the estrous cycle and early pregnancy in heifers and cows. We used flow cytometry and RT-qPCR to assess protein and mRNA expression of molecules important for immune function. We observed that monocytes and T cells were most affected by pregnancy status in heifers, whereas, CD8+ lymphocytes and natural killer (NK) cells were most affected during early pregnancy in cows. Changes in immune parameters measured appeared to be greater in heifers than cows including changes in expression of numerous immune function molecules. To test the hypothesis, we conducted a third experiment to simultaneously analyze the immunological responses to pregnancy between cows and heifers. We observed that cows had greater expression of proinflammatory cytokines and molecules associated with leukocyte migration and phagocytosis compared to heifers. Moreover, animals that failed to become pregnant showed altered expression of anti-inflammatory molecules. Overall, these findings support the hypothesis that early pregnancy signaling alters the proportions and functions of peripheral blood immune cells and differences between cows and heifers may yield insight into the reduced fertility of mature lactating dairy cows.

The development of therapeutic approaches for the induction of robust, long-lasting and antigen-specific immune tolerance remains an important unmet clinical need for the management of autoimmunity, allergy, organ transplantation and gene therapy. Recent breakthroughs in our understanding of immune tolerance mechanisms have opened new research avenues and therapeutic opportunities in this area. Here, we review mechanisms of immune tolerance and novel methods for its therapeutic induction.

Aim: To elucidate dynamics and functions in colonic macrophage subsets, and their regulation by Bifidobacterium breve (B. breve) and its associated metabolites in the initiation of colitis-associated colorectal cancer (CAC). Methods: Azoxymethane (AOM) and dextran sodium sulfate (DSS) were used to create a CAC model. The tumor-suppressive effect of B. breve and variations of macrophage subsets were evaluated. Intestinal macrophages were ablated to determine their role in the protective effects of B. breve. Efficacious molecules produced by B. breve were identified by non-targeted and targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The molecular mechanism was further verified in murine bone marrow-derived macrophages (BMDMs), macrophages derived from human peripheral blood mononuclear cells (hPBMCs), and demonstrated in CAC mice. Results: B. breve alleviated colitis symptoms, delayed colonic tumorigenesis, and promoted phenotypic differentiation of immature inflammatory macrophages into mature homeostatic macrophages. On the contrary, the ablation of intestinal macrophages largely annulled the protective effects of B. breve. Microbial analysis of colonic contents revealed the enrichment of probiotics and the depletion of potential pathogens following B. breve supplementation. Moreover, indole-3-lactic acid (ILA) was positively correlated with B. breve in CAC mice and highly enriched in the culture supernatant of B. breve. Also, the addition of ILA directly promoted AKT phosphorylation and restricted the pro-inflammatory response of murine BMDMs and macrophages derived from hPBMCs in vitro. The effects of ILA in murine BMDMs and macrophages derived from hPBMCs were abolished by the aryl hydrocarbon receptor (AhR) antagonist CH-223191 or the AKT inhibitor MK-2206. Furthermore, ILA could protect against tumorigenesis by regulating macrophage differentiation in CAC mice; the AhR antagonist largely abrogated the effects of B. breve and ILA in relieving colitis and tumorigenesis. Conclusion: B. breve-mediated tryptophan metabolism ameliorates the precancerous inflammatory intestinal milieu to inhibit tumorigenesis by directing the differentiation of immature colonic macrophages.

Aryl hydrocarbon receptor (AHR) signalling integrates biological processes that sense and respond to environmental, dietary, and metabolic challenges to ensure tissue homeostasis. AHR is a transcription factor that is inactive in the cytosol but upon encounter with ligand translocates to the nucleus and drives the expression of AHR targets, including genes of the cytochrome P4501 family of enzymes such as Cyp1a1. To dynamically visualise AHR activity in vivo, we generated reporter mice in which firefly luciferase (Fluc) was non-disruptively targeted into the endogenous Cyp1a1 locus. Exposure of these animals to FICZ, 3-MC or to dietary I3C induced strong bioluminescence signal and Cyp1a1 expression in many organs including liver, lung and intestine. Longitudinal studies revealed that AHR activity was surprisingly long-lived in the lung, with sustained Cyp1a1 expression evident in discrete populations of cells including columnar epithelia around bronchioles. Our data link diet to lung physiology and also reveal the power of bespoke Cyp1a1-Fluc reporters to longitudinally monitor AHR activity in vivo.

Arginine and tryptophan are pivotal in orchestrating cytokine-driven macrophage polarization and immune activation. Specifically, interferon-gamma (IFN-γ) stimulates inducible nitric oxide synthase (iNOS) expression), leading to the conversion of arginine into citrulline and nitric oxide (NO), while Interleukin-4 (IL4) promotes arginase activation, shifting arginine metabolism toward ornithine. Concomitantly, IFN-γ triggers indoleamine 2,3-dioxygenase 1 (IDO1) and Interleukin-4 induced 1 (IL4i1), resulting in the conversion of tryptophan into kynurenine and indole-3-pyruvic acid. These metabolic pathways are tightly regulated by NAD+-dependent sirtuin proteins, with Sirt2 and Sirt5 playing integral roles. In this review, we present novel insights that augment our understanding of the metabolic pathways of arginine and tryptophan following Mycobacterium tuberculosis infection, particularly their relevance in macrophage responses. Additionally, we discuss arginine methylation and demethylation and the role of Sirt2 and Sirt5 in regulating tryptophan metabolism and arginine metabolism, potentially driving macrophage polarization.

Aryl hydrocarbon receptor (AhR) was originally identified as an environmental sensor that responds to pollutants. Subsequent research has revealed that AhR recognizes multiple exogenous and endogenous molecules, including uremic toxins retained in the body due to the decline in renal function. Therefore, AhR is also considered to be a uremic toxin receptor. As a ligand-activated transcriptional factor, the activation of AhR is involved in cell differentiation and senescence, lipid metabolism and fibrogenesis. The accumulation of uremic toxins in the body is hazardous to all tissues and organs. The identification of the endogenous uremic toxin receptor opens the door to investigating the precise role and molecular mechanism of tissue and organ damage induced by uremic toxins. This review focuses on summarizing recent findings on the role of AhR activation induced by uremic toxins in chronic kidney disease, diabetic nephropathy and acute kidney injury. Furthermore, potential clinical approaches to mitigate the effects of uremic toxins are explored herein, such as enhancing uremic toxin clearance through dialysis, reducing uremic toxin production through dietary interventions or microbial manipulation, and manipulating metabolic pathways induced by uremic toxins through controlling AhR signaling. This information may also shed light on the mechanism of uremic toxin-induced injury to other organs, and provide insights into clinical approaches to manipulate the accumulated uremic toxins.

Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer. Despite decades of intense investigation, treatment options remain limited, and rapid recurrence with distant metastases remains a significant challenge. Cancer cell-intrinsic production of cytokines such as type I interferons (IFN-I) is a known potent modulator of response to therapy in many cancers, including TNBC, and can influence therapeutic outcome. Here, we report that, in TNBC systems, the aryl hydrocarbon receptor (AhR) suppresses IFN-I expression via inhibition of STImulator of Interferon Genes (STING), a key mediator of interferon production. Intratumoral STING activity is essential in mediating the efficacy of PARP inhibitors (PARPi) which are used in the treatment of cancers harboring BRCA1 deficiency. We find that, in TNBC cells, PARPi treatment activates AhR in a BRCA1 deficiency-dependent manner, thus suggesting the presence of a negative feedback loop aimed at modulating PARPi efficacy. Importantly, our results indicate that the combined inhibition of PARP and AhR is superior in elevating IFN-I expression as compared to PARPi-alone. Thus, AhR inhibition may allow for enhanced IFN-I production upon PARPi in BRCA1-deficient breast cancers, most of which are of TNBC origin, and may represent a therapeutically viable strategy to enhance PARPi efficacy.

Considering the role of T helper (Th)17 cells in the pathogenesis of ankylosing spondylitis (AS), the aim of this study was to determine the correlation between aryl hydrocarbon receptor (AHR) gene expression and the expression of Th17-related genes including interleukin (IL)-17 and RAR-related orphan receptor gamma t (RORγt) transcription factor.

Thirty patients with AS (26 males, 4 females; mean age: 36.1±8.1 years) and 30 age- and sex-matched healthy individuals (26 males, 4 females; mean age: 36.2±14.6 years) were recruited for the case-control study between June 2021 and January 2022. Ribonucleic acid (RNA) was extracted from peripheral blood cells and expression levels of AHR, IL-17, RORγt, and AHR repressor (AHRR) genes were evaluated using real-time polymerase chain reaction technique. The serum level of IL-17 was evaluated with enzyme-linked immunosorbent assay.

The results showed a nonsignificant elevation of AHR, IL-17, and RORγt gene expression in the patient group compared to the control. There was a direct correlation between AHR gene expression and IL-17 and RORγt genes and a negative correlation between AHR and AHRR expression. Moreover, AHR gene expression showed a weak correlation with disease activity indices, including Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Global Score, and Ankylosing Spondylitis Quality of Life. Moreover, the serum level of IL-17 was higher in AS patients compared to the healthy group (p=0.02).

Upregulated expression of the AHR gene in ankylosing spondylitis and its correlation with IL-17 and ROR-γ t gene expression suggests that it could be a potential diagnostic and therapeutic target for AS.

Indole-3-carbinol(I3C) is a tumor chemopreventive substance that can be extracted from cruciferous vegetables. Indole-3-carbinol (I3C) has been shown to have antioxidant and anti-inflammatory effects. In this study, we investigated the cerebral protective effects of I3C in an in vivo rats model of middle cerebral artery occlusion (MCAO). 8-10 Week-Old male SD rat received I3C (150 mg/kg, once daily) for 3 days and underwent 3 h of middle cerebral artery occlusion (MCAO) followed by reperfusion. The results showed that I3C pretreatment (150 mg/kg, once daily) prevented CIRI-induced cerebral infarction in rats. I3C pretreatment also decreased the mRNA expression levels of several apoptotic proteins, including Bax, caspase-3 and caspase-9, by increasing the mRNA expression levels of the anti-apoptotic protein Bcl-2. Inhibited apoptosis in the brain cells of MCAO rats. In addition, we found that I3C pretreatment reduced neuronal loss, promoted neurological recovery after ischemia-reperfusion injury and increased seven-day survival in MCAO rats. I3C pretreatment also significantly reduced the expression of inducible nitric oxide synthase (INOS), interleukin-1β (IL-1β) and interleukin-6 (IL-6) mRNA in ischemic brain tissue; Increased expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) mRNA. At the same time, I3C pretreatment significantly decreased the expression of the M1 microglial marker IBA1 after cerebral ischemia-reperfusion injury and increased the expression of these results in the M2 microglial marker CD206. I3C pretreatment also significantly decreased apoptosis and death of HAPI microglial cells after hypoxia induction, decreased interleukin-1β (IL-1β) and interleukin-6 (IL-6) mRNA The expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) mRNAs was increased. These results suggest that I3C protects the brain from CIRI by regulating the anti-inflammatory and anti-apoptotic effects of microglia.

Clearance of multiple rounds of apoptotic cells (ACs) through continual efferocytosis is critical in the maintenance of organ function, the resolution of acute inflammation, and tissue repair. To date, little is known about the nature of mechanisms and factors that govern this fundamental process. Herein, the authors reported that breakdown of ACs leads to upregulation of 12-lipoxygenase in macrophages. This enzyme converts docosahexaenoic acid to maresin conjugates in tissue regeneration (MCTRs). The levels of these autacoids are elevated at sites of high apoptotic burden in vivo and in efferocytosing macrophages in vitro. Abrogation of MCTR production using genetic approaches limits the ability of macrophages to perform continual efferocytosis both in vivo and in vitro, an effect that is rescued by add-back of MCTRs. Mechanistically, MCTR-mediated priming of macrophages for continual efferocytosis is dependent on alterations in Rac1 signalling and glycolytic metabolism. Inhibition of Rac1 abolishes the ability of MCTRs to increase glucose uptake and efferocytosis in vitro, whereas inhibition of glycolysis limits the MCTR-mediated increases in efferocytosis and tissue repair. Together, these findings demonstrate that upregulation of MCTRs by efferocytosing macrophages plays a central role in the regulation of continual efferocytosis via the autocrine and paracrine modulation of metabolic pathways.

Aryl hydrocarbon receptor (AhR) responds to endogenous and exogenous ligands as a cytosolic receptor, transcription factor, and E3 ubiquitin ligase. Several studies support an anti-inflammatory effect of AhR activation. However, exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early stages of development results in an autoimmune phenotype and exacerbates lupus. The effects of TCDD on lupus in adults with pre-existing autoimmunity have not been described. We present novel evidence that AhR stimulation by TCDD alters T cell responses but fails to impact lupus-like disease using an adult mouse model. Interestingly, AhR antagonist CH223191 also changed T cell balance in our model. We next developed a conceptual framework for identifying cellular and molecular factors that contribute to physiological outcomes in lupus and created models that describe cytokine dynamics that were fed into a system of differential equations to predict the kinetics of T follicular helper (Tfh) and regulatory T (Treg) cell populations. The model predicted that Tfh cells expanded to larger values following TCDD exposure compared with vehicle and CH223191. Following the initial elevation, both Tfh and Treg cell populations continuously decayed over time. A function based on the ratio of predicted Treg/Tfh cells showed that Treg cells exceed Tfh cells in all groups, with TCDD and CH223191 showing lower Treg/Tfh cell ratios than the vehicle and that the ratio is relatively constant over time. We conclude that AhR ligands did not induce an anti-inflammatory response to attenuate autoimmunity in adult lupus mice. This study challenges the dogma that TCDD supports an immunosuppressive phenotype.