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[This corrects the article DOI: 10.3389/fimmu.2026.1724948.].

Besnoitia besnoiti is an obligate intracellular apicomplexan protozoan parasite, which causes bovine besnoitiosis. Recently increased emergence within Europe was responsible for significant economic losses in the cattle industry due to the significant reduction of productivity. However, still limited knowledge exists on interactions between B. besnoiti and host innate immune system. Here, B. besnoiti bradyzoites were successfully isolated from tissue cysts located in skin biopsies of a naturally infected animal, and we aimed to investigate for the first time reactions of polymorphonuclear neutrophils (PMN) exposed to these vital bradyzoites. Freshly isolated bovine PMN were confronted to B. besnoiti bradyzoites. Scanning electron microscopy (s.e.m.)- and immunofluorescence microscopy-analyses demonstrated fine extracellular networks released by exposed bovine PMN resembling suicidal NETosis. Classical NETosis components were confirmed via co-localization of extracellular DNA decorated with histone 3 (H3) and neutrophil elastase (NE). Live cell imaging by 3D holotomographic microscopy (Nanolive®) unveiled rapid vital NETosis against this parasite. A significant increase of autophagosomes visualized by specific-LC3B antibodies and confocal microscopy was observed in B. besnoiti-stimulated bovine PMN when compared to non-stimulated group. As such, a significant positive correlation (r = 0.37; P = 0.042) was found between B. besnoiti-triggered suicidal NETosis and autophagy. These findings suggest that vital- as well as suicidal-NETosis might play a role in early innate host defence mechanisms against released B. besnoiti bradyzoites from tissue cysts, and possibly hampering further parasitic replication. Our data generate first hints on autophagy being associated with B. besnoiti bradyzoite-induced suicidal NETosis and highlighting for first time occurrence of parasite-mediated vital NETosis.

Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients’ blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease.

L-selectin (CD62L) is a type-I transmembrane glycoprotein and cell adhesion molecule that is expressed on most circulating leukocytes. Since its identification in 1983, L-selectin has been extensively characterized as a tethering/rolling receptor. There is now mounting evidence in the literature to suggest that L-selectin plays a role in regulating monocyte protrusion during transendothelial migration (TEM). The N-terminal calcium-dependent (C-type) lectin domain of L-selectin interacts with numerous glycans, including sialyl Lewis X (sLe ) for tethering/rolling and proteoglycans for TEM. Although the signals downstream of L-selectin-dependent adhesion are poorly understood, they will invariably involve the short 17 amino acid cytoplasmic tail. In this review we will detail the expression of L-selectin in different immune cell subsets, and its influence on cell behavior. We will list some of the diverse glycans known to support L-selectin-dependent adhesion, within luminal and abluminal regions of the vessel wall. We will describe how each domain within L-selectin contributes to adhesion, migration and signal transduction. A significant focus on the L-selectin cytoplasmic tail and its proposed contribution to signaling via the ezrin-radixin-moesin (ERM) family of proteins will be outlined. Finally, we will discuss how ectodomain shedding of L-selectin during monocyte TEM is essential for the establishment of front-back cell polarity, bestowing emigrated cells the capacity to chemotax toward sites of damage.

Neutrophils (polymorphonuclear leukocytes, PMN) are abundant innate immune cells that rapidly accumulate at mucosal surfaces during inflammation. While their antimicrobial functions are essential for host defense, sustained PMN activation profoundly alters the tissue microenvironment, driving epithelial barrier disruption, ECM remodeling, metabolic imbalance, and microbiome dysbiosis. In chronic inflammatory diseases such as inflammatory bowel disease (IBD), these processes contribute to persistent tissue injury and therapeutic resistance. In this review, we synthesize evidence from human mucosal biopsies, experimental models of intestinal inflammation, and emerging single-cell, spatial, and metabolic approaches to define how PMN shape the inflamed mucosal microenvironment. We highlight mechanisms governing PMN recruitment, retention, and survival; effector programs including reactive oxygen species production, protease release, and PMN extracellular trap formation; and bidirectional crosstalk with epithelial, stromal, and immune cell compartments. We further discuss how PMN-driven metabolic and microbiome alterations reinforce chronic inflammation and influence responses to biologic therapy. Collectively, these insights reframe PMN as context-dependent regulators of mucosal pathology and repair and identify PMN-centered pathways as promising targets for precision therapies aimed at restoring barrier function and promoting durable inflammatory resolution.

We present the development of a 6 × 6 piezoelectric array sensor for measuring elasticity and force. The proposed sensor employs an impedance measurement technique, sensing the acoustic load impedance of a target by measuring the electrical impedance shift of face-shear mode PMN–PT (lead magnesium niobate–lead titanate) single crystal elements. Among various modes of PMN–PT single crystals, the face-shear mode was selected due to its especially high sensitivity to acoustic loads. To verify the elasticity sensing performance, gelatin samples with different elastic moduli were prepared and tested. For the force measurement test, different magnitudes of force were loaded to the sensing layer whose acoustic impedance was varied with applied forces. From the experimental results, the fabricated sensor showed an elastic stiffness sensitivity of 23.52 Ohm/MPa with a resolution of 4.25 kPa and contact force sensitivity of 19.27 Ohm/N with a resolution of 5.19 mN. In addition, the mapping experiment of elasticity and force using the sensor array was successfully demonstrated.

The main objective of the present study was to investigate the hemo and immune compatibility of gliadin nanoparticles as a function of particle size. Gliadin nanoparticles of different size were prepared using a modified antisolvent nanoprecipitation method. The hemolytic potential of gliadin nanoparticles was evaluated using in vitro hemolysis assay. Phagocytic uptake of gliadin nanoparticles was studied using rat polymorphonuclear (PMN) leukocytes and murine alveolar peritoneal macrophage (J774) cells. In vivo immunogenicity of gliadin nanoparticles was studied following subcutaneous administration in mice. Gliadin nanoparticles were non-hemolytic irrespective of particle size and hence compatible with blood components. In comparison to positive control zymosan, gliadin nanoparticles with a size greater than 406 ± 11 nm showed higher phagocytic uptake in PMN cells, while the uptake was minimal with smaller nanoparticles (127 ± 8 nm). Similar uptake of gliadin nanoparticles was observed in murine alveolar peritoneal macrophages. Anti-gliadin IgG antibody titers subsequent to primary and secondary immunization of gliadin nanoparticles in mice were in the increasing order of 406 ± 11 nm < 848 ± 20 nm < coarse suspension). On the other hand, gliadin nanoparticles of 127 ± 8 nm in size did not elicit immunogenic response. Phagocytosis and immunogenicity of gliadin nanoparticles are strongly influenced by particle size. The results of this study can provide useful information for rational design of protein-based nanomaterials in drug delivery applications.

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.

Neutrophils have been extensively described in the pathophysiology of autoimmune and infectious diseases. Accumulating evidence also suggests the important role of neutrophils in cancer progression through their interaction with cancer and immune cells in blood and in the tumor microenvironment (TME). Most studies have described neutrophils as key drivers of cancer progression, due to their involvement in various tumor promoting functions including proliferation, aggressiveness, and dissemination, as well as in immune suppression. However, such studies were focusing on late-stages of tumorigenesis, in which chronic inflammation had already developed. The role of tumor-associated neutrophils (TANs) at early stages of tumor development remains poorly described, though recent findings indicate that early-stage TANs may display anti-tumor properties. Beyond their role at tumor site, evidence supported by NLR retrospective studies and functional analyses suggest that blood neutrophils could also actively contribute to tumorigenesis. Hence, it appears that the phenotype and functions of neutrophils vary greatly during tumor progression, highlighting their heterogeneity. The origin of pro- or anti-tumor neutrophils is generally believed to arise following a change in cell state, from resting to activated. Moreover, the fate of neutrophils may also involve distinct differentiation programs yielding various subsets of pro or anti-tumor neutrophils. In this review, we will discuss the current knowledge on neutrophils heterogeneity across different tissues and their impact on tumorigenesis, as well as neutrophil-based therapeutic strategies that have shown promising results in pre-clinical studies, paving the way for the design of neutrophil-based next generation immunotherapy.

Myeloid‐derived suppressor cells (MDSCs) are responsible for antitumor immunodeficiency in tumor‐bearing hosts. Primarily, MDSCs are classified into 2 groups: monocytic (M)‐MDSCs and polymorphonuclear (PMN)‐MDSCs. In most cancers, PMN‐MDSCs (CD11b+Ly6ClowLy6G+ cells) represent the most abundant MDSC subpopulation. However, the functional and phenotypic heterogeneities of PMN‐MDSC remain elusive, which delays clinical therapeutic targeting decisions. In the 4T1 murine tumor model, CD11b+Ly6Glow PMN‐MDSCs were sensitive to surgical and pharmacological interventions. By comprehensively analyzing 64 myeloid cell‐related surface molecule expression profiles, cell density, nuclear morphology, and immunosuppressive activity, the PMN‐MDSC population was further classified as CD11b+Ly6GlowCD205+ and CD11b+Ly6GhighTLR2+ subpopulations. The dichotomy of PMN‐MDSCs based on CD205 and TLR2 is observed in 4T07 murine tumor models (but not in EMT6). Furthermore, CD11b+Ly6GlowCD205+ cells massively accumulated at the spleen and liver of tumor‐bearing mice, and their abundance correlated with in situ tumor burdens (with or without intervention). Moreover, we demonstrated that CD11b+Ly6GlowCD205+ cells were sensitive to glucose deficiency and 2‐deoxy‐d‐glucose (2DG) treatment. Glucose transporter 3 (GLUT3) knockdown by siRNA significantly triggered apoptosis and reduced glucose uptake in CD11b+Ly6GlowCD205+ cells, demonstrating the dependence of CD205+ PMN‐MDSCs survival on both glucose uptake and GLUT3 overexpression. As GLUT3 has been recognized as a target for the rescue of host antitumor immunity, our results further directed the PMN‐MDSC subsets into the CD205+GLUT3+ subpopulation as future targeting therapy. We confirmed that CD205+ PMN‐MDSCs were potent immunosuppressive cells in vitro as well as in vivo and sensitive to glucose deficiency and 2‐deoxy‐D‐glucose (2DG) treatment in vitro. GLUT3 knockdown by siRNA significantly reduced the survival and glucose uptake rate of CD205+ PMN‐MDSCs and markedly retarded transplanted 4T1 tumor growth. Our results implications that PMN‐MDSC subsets in peripheral organs are also phenotypically and functionally heterogeneous, and glucose metabolism patterns profoundly affected the anti‐tumor immunity.