Explore the vast range of titles available.

Mouse CCL8 is a CC chemokine of the monocyte chemoattractant protein (MCP) family whose biological activity and receptor usage have remained elusive. Here we show that CCL8 is highly expressed in the skin, where it serves as an agonist for the chemokine receptor CCR8 but not for CCR2. This distinguishes CCL8 from all other MCP chemokines. CCL8 responsiveness defined a population of highly differentiated, CCR8-expressing inflammatory T helper type 2 (T(H)2) cells enriched for interleukin (IL)-5. Ccr8- and Ccl8-deficient mice had markedly less eosinophilic inflammation than wild-type or Ccr4-deficient mice in a model of chronic atopic dermatitis. Adoptive transfer studies established CCR8 as a key regulator of T(H)2 cell recruitment into allergen-inflamed skin. In humans, CCR8 expression also defined an IL-5-enriched T(H)2 cell subset. The CCL8-CCR8 chemokine axis is therefore a crucial regulator of T(H)2 cell homing that drives IL-5-mediated chronic allergic inflammation.

The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP + exosomes. Moreover, uptake of CEMIP + exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2 , Tnf and Ccl/Cxcl , known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis. Rodrigues et al. show that exosomal CEMIP derived from brain metastatic cells elicits vascular remodelling and inflammation and supports subsequent metastatic colonization in the brain microenvironment.

BackgroundSince the lung is one of the most common sites for cancer metastasis, it could provide a suitable microenvironment for pre-metastatic niche (PMN) formation to facilitate tumor cell colonization. Regulatory T cells (Tregs) are an immunosuppressive cell type found ubiquitously in tumors and may play a crucial role in PNM formation. In this study, we investigated tumor-derived exosome (TDE)-induced Treg differentiation in the lung PMN as well as the underlying mechanisms.MethodsTDEs were isolated from the Lewis lung carcinoma cell line (LLC-exo) and their effects on mouse pulmonary fibroblasts was investigated in vitro as well as on lung tumor formation and metastasis in a pre-injected mouse model. Immune cell populations in the lung were analyzed by flow cytometry. Expression of CCL1 and CCR8 was evaluated by immunofluorescence staining, qRT-PCR and Western blot analyses. Cytokine expression was measured using mouse cytokine arrays and ELISA.ResultsThe number of CD4+ FoxP3+ Tregs was significantly increased in lungs in a LLC-exo pre-injected mouse model. Lung fibroblasts secreted increased amounts of CCL1 after co-culture with LLC-exo, which induced Treg differentiation by activating its specific receptor CCR8, ultimately contributing to the establishment of an immunologically tolerant PMN. Moreover, inhibiting the release of LLC-exo by GW4869, or blocking the CCL1-CCR8 axis using AZ084, suppressed Tregs differentiation and tumor metastasis in the lung.ConclusionsCollectively, our study provides a novel mechanism by which Tregs are activated to form an immunologically tolerant PMN and demonstrates a critical link among lung fibroblasts, Tregs and metastatic tumor cells.

Echinococcus multilocularis ( E. m ) infection causes alveolar echinococcosis (AE), a serious zoonotic disease characterized by invasive larval growth in the liver. The parasite establishes a chronic infection, suggesting effective modulation of host immunity. Here, we investigated the role of the CCR8/CCL1 chemokine axis in shaping the hepatic immune microenvironment during E.m infection. In infected wild-type (WT) mice, chronic infection specifically activated the hepatic CCR8/CCL1 axis, which was associated with a marked accumulation of FOXP3 + regulatory T cells (Tregs). Notably, although CCR8 + T cells expanded numerically, their production of effector (IFN-γ, TNF-α, and perforin) was significantly impaired. In contrast, infected CCR8-knockout (KO) mice developed smaller hepatic lesions, exhibited a reduction in liver weight, and had significantly lower serum ALT levels. Mechanistically, CCR8 deficiency enhanced the effector functions of CD4 + and CD8 + T cells, skewing the immune response towards a Th1 phenotype, and partially reversed the immunosuppressive milieu. Our findings establish that the CCR8/CCL1 axis drives the formation of an immunosuppressive niche in the liver by recruiting both Tregs and functionally suppressed CCR8 + T cells, thereby facilitating parasite immune evasion. This study not only elucidates a pivotal mechanism of immune escape in AE but also identifies CCR8 as a promising novel immunotherapeutic target for this neglected tropical disease.

This paper discussed the role of AlkB homologue 5 (Alkbh5) in the progression of lipopolysaccharide (LPS)‐induced acute lung injury (ALI). LPS‐induced ALI models were established in Alkbh5 knockout (KO) and knock‐in (KI) mice. The m6A levels in lung tissues were analysed using m6A dot assays. The lung injury was analysed by determining ALI‐related markers and histological staining. Mouse MLE12 cells were exposed to LPS for in vitro experiments, and the influence of Alkbh5 on cell viability, apoptosis and reactive oxygen species (ROS) production was analysed. RNA‐seq analysis was performed to analyse gene changes upon Alkbh5 deficiency. Functions of the Alkbh5‐C‐C motif chemokine ligand 1 (Ccl1) cascade in ALI were further verified using the Alkbh5 antagonist DDO‐2728 and a recombinant protein of Ccl1 (mCcl1). Alkbh5 was upregulated in lung tissues following LPS exposure. Alkbh5 knockout in mice mitigated LPS‐induced lung injury, as indicated by reduced serum levels of lung injury markers and reduced immune cell infiltration, fibrosis and apoptosis. Conversely, Alkbh5 overexpression in mice resulted in reverse trends. In vitro, Alkbh5 knockdown in MLE12 cells enhanced cell viability while reducing cell apoptosis and ROS production. Mechanistically, Alkbh5 was found to bind to and destabilise Ccl1 mRNA, leading to increased Treg recruitment. Treatment with DDO‐2728 or mCcl1 in mice increased Treg infiltration, thus improving lung tissue pathology and reducing lung injury. This study suggests that Alkbh5 is implicated in ALI progression by reducing Ccl1‐mediated Treg recruitment, making it a promising target for ALI management. In septic lung injury mice, Alkbh5 is highly expressed, promoting the demethylation of m6A on Ccl1 mRNA, thereby reducing the stability of Ccl1 mRNA and decreasing Ccl1 expression. This, in turn, leads to reduced recruitment of Tregs, further exacerbating the symptoms of septic lung injury. The findings from this study suggest that Alkbh5‐mediated m6A demethylation plays a crucial role in modulating the inflammatory response in sepsis‐associated ALI by affecting Ccl1 mRNA stability and Treg dynamics. These insights contribute to a deeper understanding of the molecular mechanisms underlying sepsis‐induced ALI and highlight potential therapeutic strategies targeting m6A modifications to regulate immune responses in sepsis and other inflammatory diseases.

The airway epithelial barrier is the first defence against aeroallergens. Nasal epithelial cells (NECs) are vital in regulating innate and adaptive mucosal immunity in allergic rhinitis (AR). Tregs produce cytokines essential for the immunomodulatory activities in allergen immunotherapy. Understanding the relationship between NECs and Tregs in the airway hyperresponsiveness network is essential for developing novel treatments. Using an human Treg-NEC co-culture system of AR and health control group, the chemokine expression profiles of NECs were examined using immunohistochemistry, RT-PCR, and ELISA, and functional surface markers of Tregs were detected using flow cytometric analysis. Correlation analysis was performed between cytokines derived from NECs and surface markers of CD4+CD8+Foxp3+ Tregs in the AR group after co-culture, including TSLP/CTLA4, CCL1/CTLA4, TSLP/CTLA4, TSLP/CCR8, and CCL1/CCR8. CCR8 and CTLA-4 expressions after co-culturing were higher than single culture. Following Derp1 stimulation, TSLP, IL-25 and TGF-β expressions in the AR + Derp1 group were increased. CCL1 mRNA was lower in the AR + Derp1 group than control group. In the AR + Derp1 group, TSLP was higher, and CCL1 protein levels were decreased. There were no significant differences in IL-25, TGF-β and IL-10. When Treg co-culture group added, changes were similar to that observed in pNECs. After co-culture, CCL1/CCR8 was positively correlated in AR. Human pNECs can communicate with Tregs directly, CCL1/CCR8 may be the pathway between NECs and Tregs and may play a key role in the immune network of AR.

Colorectal cancer (CRC) liver metastasis, albeit a stage‐IV disease, is completely curable by surgical resection in selected patients. In addressing the molecular basics of this phenomenon, differentially expressed genes at primary and liver metastatic sites were screened by RNA sequencing with the use of paraffin‐embedded surgical specimens. Chemokine C‐C motif ligand 1 (CCL1), a chemotactic factor for a ligand of the chemokine C‐C motif receptor 8 (CCR8), was isolated as one of the differentially expressed genes. Histological analysis revealed that the number of CCL1‐positive cells, mainly tumour associated macrophages (TAMs) located in the stroma of CRC, decreased significantly at liver metastatic sites, while the expression level of CCR8 on CRC remained unchanged. To explore the biological significance of the CCL1‐CCR8 axis in CRC, CCR8‐positive CRC cell line Colo320DM was used to assess the effect of the CCL1‐CCR8 axis on major signalling pathways, epithelial mesenchymal transition induction and cell motility. Upon stimulation of recombinant CCL1 (rCCL1), phosphorylation of AKT was observed in Colo320DM cells; on the other hand, the corresponding significant increase in MMP‐2 levels demonstrated by RT‐qPCR was nullified by siRNA (siCCR8). In the scratch test, rCCL1 treatment significantly increased the motility of Colo320DM cells, which was similarly nullified by siCCR8. Thus, the activation of the CCL1‐CCR8 axis is a positive regulator of CRC tumour progression. Reduced CCL1 expression of TAMs at liver metastatic sites may partly explain the unique slow tumour progression of CRC, thus providing for a grace period for radical resection of metastatic lesions.

Differentiating between infectious and non-infectious etiologies in systemic inflammatory disorders may be challenging due to overlapping clinical presentations and the lack of reliable discriminating biomarkers. Regulatory T-cells (Tregs) modulate immune responses. Their functionality is governed by specific chemokines, including CCL1 and CCL22. We investigated whether these Treg-attracting chemokines are differentially regulated in infectious versus sterile inflammation. This prospective, single-center biomarker study enrolled patients with sepsis, acute pancreatitis, and hospitalized controls without infectious diseases. Serum samples were collected on days 1, 3, 5, and 7, measuring CRP, IL-6, PCT, CCL1, and CCL22. Between March 2019 and October 2022, 159 patients were enrolled, comprising 45 patients suffering from acute pancreatitis, 15 patients with confirmed sepsis as well as 99 hospitalized controls. Established inflammatory parameters CRP, IL-6 and PCT showed typical kinetics. Decreased CCL1 levels, but not CCL22, distinguished acute pancreatitis from sepsis at all time points. Additionally, CCL1 levels inversely correlated with organ failure severity in sepsis patients. CCL1 shows potential to serve as a biomarker to differentiate sterile and non-sterile inflammation in sepsis and acute pancreatitis. This may support clinical decision-making and allow a more precise use of antibiotics in these patient cohorts.

Background Regulatory T cells (Treg) suppress cytotoxic T cell anti-tumoral immune responses and thereby promote tumor progression. Prevention of intratumoral Treg accumulation by inhibition of their migration to the tumor microenvironment is a promising therapeutic strategy. The aim of this study was to identify the role of the two major Treg-attracting chemokines CCL1 and CCL22 in human breast cancer. Methods One hundred ninety-nine tissue samples of patients with invasive breast cancer were stained for CCL1 and CCL22 by immunohistochemistry. Chemokine expression and tumor infiltration by regulatory T cells, determined by expression of the transcription factor FoxP3, were quantified and their correlation to clinical features was statistically analyzed. Results Both CCL1 and CCL22 were expressed in most breast cancer tissues. CCL1 was significantly over-expressed in invasive breast cancer as compared to normal breast tissue. CCL1, but surprisingly not CCL22, showed a significant correlation with the number of tumor-infiltrating FoxP3+ Treg ( p < 0.001). High numbers of intratumoral CCL1 expressing cells were related to high grade tumors (G4) and a positive estrogen receptor (ER) status whereas high CCL22 expression was generally seen in lower grade tumors. The median survival of 88 patients with high intratumoral CCL1 expression was 37 months compared to 50 months for the 87 patients with low CCL1 levels, this trend was however not statistically significant. Conclusions We found a high expression of CCL1 in human breast cancer. CCL1 significantly correlated with the infiltration of immunosuppressive FoxP3+ Treg, that are known to negatively affect survival. Thus, CCL1 may serve as prognostic marker and novel therapeutic target in breast cancer.

In addition to maintaining immune tolerance, FOXP3 + regulatory T (T reg ) cells perform specialized functions in tissue homeostasis and remodelling 1 , 2 . However, the characteristics and functions of brain T reg cells are not well understood because there is a low number of T reg cells in the brain under normal conditions. Here we show that there is massive accumulation of T reg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain T reg cells are similar to T reg cells in other tissues such as visceral adipose tissue and muscle 3 – 5 , they are apparently distinct and express unique genes related to the nervous system including Htr7 , which encodes the serotonin receptor 5-HT 7 . The amplification of brain T reg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain T reg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that T reg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases. In a mouse model of ischaemic stroke, regulatory T cells infiltrate the injured brain in response to the chemokines CCL1 and CCL20 and suppress excessive astrogliosis via the production of amphiregulin.