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Targeted deletion of the chemokine Cxcl12 in different bone marrow stromal cell populations shows that distinct niches exist in the bone marrow for haematopoietic stem cells and lineage-committed progenitors. Multiple stem cell niches in bone marrow The chemokine CXCL12 has an important role in maintaining haematopoietic stem cell (HSC) function. Two complementary papers in the issue of Nature study the effects of conditional deletion of Cxcl12 from candidate niche cells in the bone marrow and arrive at similar conclusions despite using different cre and Cxcl12 alleles. Lei Ding and Sean Morrison map CXCL12 expression in different (putative) niche components of the adult mouse bone marrow, showing that deletion of Cxcl12 from endothelial cells, but not Lepr – cre -targeted perivascular stromal cells, contributes to HSC maintenance. These niches do not overlap, indicating compartmentalization in the bone marrow microenvironment. Daniel Link and colleagues deleted Cxcl12 from candidate niche stromal cell populations and found that expression of CXCL12 from osterix-expressing stromal cells supports B-lymphoid progenitors and retains haematopoietic progenitor cells in the bone marrow, whereas its expression from stromal cells in the perivascular region supports HSCs. These insights into the complexity of the HSC niche are of relevance to work on the development of haematopoietic disease. Haematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation and trafficking. Endosteal osteoblasts 1 , 2 and perivascular stromal cells including endothelial cells 3 , CXCL12-abundant reticular cells 4 , 5 , leptin-receptor-positive stromal cells 6 , and nestin–green fluorescent protein (GFP)-positive mesenchymal progenitors 7 have all been implicated in HSC maintenance. However, it is unclear whether specific haematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (chemokine (C–X–C motif) ligand 12) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations 7 , 8 , 9 , 10 , 11 . Here we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which include CXCL12-abundant reticular cells and osteoblasts, results in constitutive HPC mobilization and a loss of B-lymphoid progenitors, but HSC function is normal. Cxcl12 deletion from endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of C xcl12 from nestin-negative mesenchymal progenitors using Prx1–cre ( Prx1 also known as Prrx1 ) is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B-lymphoid progenitors and retains HPCs in the bone marrow, and that expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, supports HSCs.

Snail is a major transcriptional factor that induces epithelial-mesenchymal transition (EMT). In this study, we explore the effect of Snail on tumor immunity. Snail knockdown in mouse ovarian cancer cells suppresses tumor growth in immunocompetent mice, associated with an increase of CD8 + tumor-infiltrating lymphocytes and a decrease of myeloid-derived suppressor cells (MDSCs). Snail knockdown reduces the expression of CXCR2 ligands (CXCL1 and CXCL2), chemokines that attract MDSCs to the tumor via CXCR2. Snail upregulates CXCR ligands through NF-kB pathway, and most likely, through direct binding to the promoters. A CXCR2 antagonist suppresses MDSC infiltration and delays tumor growth in Snail-expressing mouse tumors. Ovarian cancer patients show elevated serum CXCL1/2, which correlates with Snail expression, MDSC infiltration, and short overall survival. Thus, Snail induces cancer progression via upregulation of CXCR2 ligands and recruitment of MDSCs. Blocking CXCR2 represents an immunological therapeutic approach to inhibit progression of Snail-high tumors undergoing EMT. Snail is a transcription factor that induces epithelial-mesenchymal transition. Here the authors show that, in the mesenchymal subtype of ovarian cancer, Snail expression promotes tumorigenesis by inducing immune evasion through CXCR2-ligands-mediated recruitment of myeloid-derived suppressor cells.

How APCs encounter T cells in the periphery remains unclear. Kabashima and colleagues show that dendritic cells form macrophage-dependent clusters in dermal perivascular areas for efficient in situ proliferation and activation of T cells. It remains largely unclear how antigen-presenting cells (APCs) encounter effector or memory T cells efficiently in the periphery. Here we used a mouse contact hypersensitivity (CHS) model to show that upon epicutaneous antigen challenge, dendritic cells (DCs) formed clusters with effector T cells in dermal perivascular areas to promote in situ proliferation and activation of skin T cells in a manner dependent on antigen and the integrin LFA-1. We found that DCs accumulated in perivascular areas and that DC clustering was abrogated by depletion of macrophages. Treatment with interleukin 1α (IL-1α) induced production of the chemokine CXCL2 by dermal macrophages, and DC clustering was suppressed by blockade of either the receptor for IL-1 (IL-1R) or the receptor for CXCL2 (CXCR2). Our findings suggest that the dermal leukocyte cluster is an essential structure for elicitating acquired cutaneous immunity.

Chemokine production by epithelial cells is important for neutrophil recruitment during viral infection, the appropriate regulation of which is critical for restraining inflammation and attenuating subsequent tissue damage. Epithelial cell expression of long noncoding RNAs (lncRNAs), RNA-binding proteins, and their functional interactions during viral infection and inflammation remain to be fully understood. Here, we identified an inducible lncRNA in the Cxcl2 gene locus, lnc-Cxcl2, which could selectively inhibit Cxcl2 expression in mouse lung epithelial cells but not in macrophages. lnc-Cxcl2–deficient mice exhibited increased Cxcl2 expression, enhanced neutrophils recruitment, and more severe inflammation in the lung after influenza virus infection. Mechanistically, nucleus-localized lnc-Cxcl2 bound to Cxcl2 promoter, recruited a ribonucleoprotein La, which inhibited the chromatin accessibility of chemokine promoters, and consequently inhibited Cxcl2 transcription in cis. However, unlike mouse lnc-Cxcl2, human lnc-CXCL2-4-1 inhibited multiple immune cytokine expressions including chemokines in human lung epithelial cells. Together, our results demonstrate a self-protecting mechanism within epithelial cells to restrain chemokine and neutrophil-mediated inflammation, providing clues for better understanding chemokine regulation and epithelial cell function in lung viral infection.

Background Gastric cancer (GC) patients frequently develop peritoneal metastasis; however, the underlying mechanism remains unknown. We hypothesised that omental adipocytes (OmAd) trigger GC cells towards malignant activity to induce peritoneal metastasis. Methods We analysed interactions among human GC cells, endothelial cells and OmAd using a 3D co-culture system. We also employed a multipronged animal study, including subcutaneous and orthotopic tumours, and humanised omental adipose tissue models. Urinary levels of CXCL2 were analysed in human GC patients with and without peritoneal metastasis. Results Conditioned media derived from OmAd (OmAd-CM) promoted the proliferation, migration and capacity to induce angiogenesis of GC cells through AKT phosphorylation and VEGFA overexpression, whereas silencing CXCL2 in OmAd cancelled OmAd-induced effects. In an orthotopic tumour model using SCID mice, omentectomy suppressed GC growth and peritoneal dissemination, and reduced serum levels of CXCL2. OmAd promoted GC growth in a humanised omental adipose tissue model using NSG mice, but silencing CXCL2 in OmAd cancelled OmAd-induced tumour growth. Finally, urinary levels of CXCL2 were significantly higher in GC patients with peritoneal metastasis than in those without. Conclusion Omental adipocytes trigger GC cells to an aggressive phenotype through CXCL2 secretion, which induces angiogenesis followed by cell growth and peritoneal metastasis.

Hepatocellular carcinoma (HCC) is a major cause of cancer‐related death worldwide. Despite the proven efficacy of immunotherapy against malignancies, a large proportion of patients with HCC fail to benefit from these efficacious agents because of their overwhelmingly immunosuppressive microenvironment. Therefore, there is an urgent need to identify key genes and develop effective strategies for reshaping the HCC microenvironment. Here, a significant downregulation of C‐X‐C motif chemokine ligand 2 (CXCL2) in HCC is identified due to gene copy number loss, which correlates with poor prognosis and suboptimal responsiveness to immunotherapy. Subsequently, it is found that CXCL2 can not only recruit neutrophils as expected, but also induce their polarization toward the antitumor type to curb HCC progression. Mechanistically, differing from the prevailing notion that CXCL2 primarily functions extracellularly as a chemokine, it is demonstrated that intracellular CXCL2 can bind to Y‐Box Binding Protein 1 (YBX1) and prevent its nuclear translocation. Consequently, this reduces the transcription of sterol regulatory element binding transcription factor 2 (SREBF2) and suppresses cholesterol biosynthesis, thereby remodeling HCC microenvironment and impeding HCC development. In summary, this study highlights the unconventional role of CXCL2 in regulating neutrophil polarization and immune responses in HCC, positioning it as a potential therapeutic target for HCC. This study identifies the unconventional role of CXCL2 in regulating neutrophil polarization and immune responses in HCC. Unlike the common view that CXCL2 acts mainly as an extracellular chemokine, intracellular CXCL2 can interact with YBX1 and prevent its nuclear translocation. This reduces SREBF2 transcriptional expression and decreases cholesterol biosynthesis, thereby reshaping the HCC microenvironment and inhibiting HCC progression.

In recent years, immune cells were shown to play critical roles in tumor growth and metastatic progression. In this context, neutrophils were shown to possess both pro- and anti-tumor properties. To exert their anti-tumor effect, neutrophils need to migrate towards, and form physical contact with tumor cells. Neutrophils secrete H2O2 in a contact-dependent mechanism, thereby inducing a lethal Ca2+ influx via the activation of the H2O2-dependent TRPM2 Ca2+ channel. Here, we explored the mechanism regulating neutrophil chemoattraction to tumor cells. Interestingly, we found that TRPM2 plays a role in this context as well, since it regulates the expression of potent neutrophil chemoattractants. Consequently, cells expressing reduced levels of TRPM2 are not approached by neutrophils. Together, these observations demonstrate how tumor cells expressing reduced levels of TRPM2 evade neutrophil cytotoxicity in two interrelated mechanisms—downregulation of neutrophil chemoattractants and blocking of the apoptotic Ca2+-dependent cascade. These observations demonstrate a critical role for TRPM2 in neutrophil-mediated immunosurveillance and identify cells expressing low levels of TRPM2, as a potential target for cancer therapy.

Triple-negative breast cancer (TNBC) is particularly aggressive, with enhanced incidence of tumor relapse, resistance to chemotherapy, and metastases. As the mechanistic basis for this aggressive phenotype is unclear, treatment options are limited. Here, we showed an increased population of myeloid-derived immunosuppressor cells (MDSCs) in TNBC patients compared with non-TNBC patients. We found that high levels of the transcription factor ΔNp63 correlate with an increased number of MDSCs in basal TNBC patients, and that ΔNp63 promotes tumor growth, progression, and metastasis in human and mouse TNBC cells. Furthermore, we showed that MDSC recruitment to the primary tumor and metastatic sites occurs via direct ΔNp63-dependent activation of the chemokines CXCL2 and CCL22. CXCR2/CCR4 inhibitors reduced MDSC recruitment, angiogenesis, and metastasis, highlighting a novel treatment option for this subset of TNBC patients. Finally, we found that MDSCs secrete prometastatic factors such as MMP9 and chitinase 3-like 1 to promote TNBC cancer stem cell function, thereby identifying a nonimmunologic role for MDSCs in promoting TNBC progression. These findings identify a unique crosstalk between ΔNp63+ TNBC cells and MDSCs that promotes tumor progression and metastasis, which could be exploited in future combined immunotherapy/chemotherapy strategies for TNBC patients.

Chronic obstructive pulmonary disease (COPD) is caused by exposure to toxic particles, such as coal fly ash (CFA), diesel-exhaust particle (DEP), and cigarette smoke (CS), leading to chronic bronchitis, mucus production, and a subsequent lung dysfunction. This study, using a mouse model of COPD, aimed to evaluate the effect of herbal combinational medication of Glycyrrhiza glabra (GG), Agastache rugosa (AR) containing glycyrrhizic acid (GA), and tilianin (TN) as active ingredients. GA, a major active component of GG, possesses a range of pharmacological and biological activities including anti-inflammatory, anti-allergic, anti-oxidative. TN is a major flavonoid that is present in AR. It has been reported to have anti-inflammatory effects of potential utility as an anti-COPD agent. The COPD in the mice model was induced by a challenge with CFA and DEP. BALB/c mice received CFA and DEP alternately three times for 2 weeks to induce COPD. The herbal mixture of GG, AR, and TN significantly decreased the number of neutrophils in the lungs and bronchoalveolar lavage (BAL) fluid. It also significantly reduced the production of C-X-C motif chemokine ligand 2 (CXCL-2), IL-17A, CXCL-1, TNF-α, symmetric dimethylarginine (SDMA) in BALF and CXCL-2, IL-17A, CXCL-1, MUC5AC, transient receptor potential vanilloid-1 (TRPV1), IL-6, COX-2, NOS-II, and TNF-α mRNA expression in the lung tissue. Notably, a combination of GG and AR was more effective at regulating such therapeutic targets than GG or AR alone. The histolopathological lung injury was alleviated by treatment with the herbal mixture and their active ingredients (especially TN). In this study, the herbal combinational mixture more effectively inhibited neutrophilic airway inflammation by regulating the expression of inflammatory cytokines and CXCL-2 by blocking the IL-17/STAT3 pathway. Therefore, a herbal mixture of GG and AR may be a potential therapeutic agent to treat COPD.

Periodontitis is clinically associated with inflammatory bowel disease (IBD), yet the shared cellular and molecular programs underpinning this oral-gut inflammatory link remain incompletely defined. We integrated bulk gingival transcriptomes from two periodontitis cohorts (GSE16134 and GSE10334) with single-cell RNA-seq data from IBD patients (51,322 cells, 18 samples). After standard quality control and batch-aware integration, we performed pseudobulk differential expression gene (DEG) analysis at the patient level to identify IBD-associated genes and intersected these with periodontitis-consensus DEGs to derive shared signatures. Cell-cell communication networks were inferred using CellChat, and gene set enrichment analysis were conducted to delineated inflammatory signaling. Myeloid subpopulations further resolved to characterize disease-associated functional states. Key findings were assessed in a dual-inflammation rodent model by immunohistochemistry. We identified 188 common DEGs across the two periodontitis cohorts and 66 genes shared in IBD, which were predominantly enriched in immune compartments and motivated a focused analysis of myeloid cells. Communication analysis revealed extensive network remodeling in IBD, with myeloid populations acting as major signaling hubs. Myeloid subclustering highlighted inflammatory and chemokine-related states characterized by high expression. Among chemokines, was prioritized because it showed consistent upregulation across bulk periodontitis transcriptomes and IBD myeloid states, and it aligned with prominent IL-1β-chemokine signaling routes inferred from intercellular communication. , IL-1β and CXCL2 signals were increased in the dual-inflammation model, supporting cross-disease consistency of this axis. Our integrative analyses identify a shared, myeloid-centered IL-1β/chemokine inflammatory program across periodontitis and IBD, which may contribute to the oral-gut inflammatory axis. The IL1β-CXCL2 pathway represents a potentially targetable signaling module, although functional blockade studies are required to establish therapeutic causality.