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Cholesterol plays an important role in cancer progression, as it is utilized in membrane biogenesis and cell signaling. Cholesterol-lowering drugs have exhibited tumor-suppressive effects in oral squamous cell carcinoma (OSCC), suggesting that cholesterol is also essential in OSCC pathogenesis. However, the direct effects of cholesterol on OSCC cells remain unclear. Here, we investigated the role of cholesterol in OSCC with respect to caveolin-1 (CAV1), a cholesterol-binding protein involved in intracellular cholesterol transport. Cholesterol levels in OSCC cell lines were depleted using methyl-β-cyclodextrin and increased using the methyl-β-cyclodextrin-cholesterol complex. Functional analysis was performed using timelapse imaging, and CAV1 expression in cholesterol-manipulated cells was investigated using immunofluorescence and immunoblotting assays. CAV1 immunohistochemistry was performed on surgical OSCC samples. We observed that cholesterol addition induced polarized cell morphology, along with CAV1 localization at the trailing edge, and promoted cell migration. Moreover, CAV1 was upregulated in the lipid rafts and formed aggregates in the plasma membrane in cholesterol-added cells. High membranous CAV1 expression in tissue specimens was associated with OSCC recurrence. Therefore, cholesterol promotes the migration of OSCC cells by regulating cell polarity and CAV1 localization to the lipid raft. Furthermore, membranous CAV1 expression is a potential prognostic marker for OSCC patients.

Neuroinflammation is a critical factor contributing to secondary brain injury following traumatic brain injury (TBI). This process engages diverse cell types within the central nervous system (CNS), including significant infiltration of myeloid lineage cells-primarily neutrophils and macrophages-during the acute and subacute phases of TBI. These myeloid-derived cells represent a major population that critically influences the development and progression of neuroinflammation. Microglia and peripherally infiltrating macrophages exhibit polarization phenotypes that play a pivotal role in modulating inflammatory changes. Due to their functional and phenotypic similarities, their distinct contributions to the inflammatory response in TBI remain a subject of considerable debate. Lysozyme 2 (Lyz2) is a well-established marker for myeloid lineage cells (including monocytes, macrophages, and neutrophils) in mice, allowing specific targeting and depletion of these cells to dissect their functional roles in TBI. In the present study, we investigated the trend of inflammatory factors during the early stage of TBI using Lyz2-IRES-DTREGFP transgenic mice, which specifically target and deplete Lyz2-positive myeloid cells. Tissue samples for RT-qPCR and flow cytometry were harvested from the perilesional cortex (within a 2-mm radius of the impact site) and the underlying hippocampus. Our findings revealed a considerable reduction in the expression of pro-inflammatory factors (e.g., IL-1β, iNOS, IL-6, IFN-γ) and an increase in the expression of anti-inflammatory factors (e.g., IL-4, IL-10, IL-13, Arg-1). Furthermore, we observed a shift in polarization phenotypes, characterized by a decreased proportion of M1 macrophages and an increased proportion of M2 macrophages. However, during the chronic phase, behavioral and histological analyses revealed worse outcomes. These findings demonstrate that targeted depletion of Lyz2-positive myeloid cells during acute TBI attenuates neuroinflammation. However, this early immunomodulatory shift correlates paradoxically with exacerbated chronic neurological deficits, suggesting that transient suppression of myeloid-driven inflammation may disrupt long-term reparative processes critical for functional recovery after TBI.

This study aimed to investigate the relationship between inflammation‐related T‐helper cell polarization and the receptor activator for nuclear factor‐κB ligand (RANKL)/osteoprotegerin (OPG) ratio, which is associated with bone resorption or remodeling of chronic periodontitis patients. Gingival crevicular fluid (GCF) and gingival tissues were obtained from periodontally healthy individuals (PH group) and chronic periodontitis patients (CP group). The GCF levels of IFN‐γ, IL‐4, IL‐17, and IL‐10 linked to T‐helper cell polarization toward the Th1, Th2, Th17, and Treg phenotypes, respectively, were determined by ELISA. The expression levels of these cytokines and the polarized T‐helper cells in gingival tissues were assessed through immunohistochemical and immunofluorescence assays. In addition, the RANKL and OPG expression levels in gingival tissues were detected by immunohistochemical assays, and linear regression analysis was used to identify the potential relationship between T‐helper cell polarization and the RANKL/OPG ratio. In total, 22 individuals and 35 patients were enrolled in the present study. In both GCF and gingival tissues, increased levels of IL‐17 and the decreased levels of IL‐4 and IL‐10 were observed in the CP group. When polarized T‐helper cells were identified in gingival tissues, more Th1 and Th17 cells were found in the CP group, whereas more Th2 and Treg cells were found in the PH group. Although there was no significant difference in OPG expression between the two groups, the RANKL/OPG ratio in the CP group was higher than that in the PH group. The linear regression analysis showed that the presence of more Th1 and Th17 cells correlated with a higher RANKL/OPG ratio, whereas the presence of more Th2 cells correlated with a lower RANKL/OPG ratio. Th1 and Th17 cells are positively correlated and Th2 cells are negatively correlated with the RANKL/OPG ratio. Our data suggest that T‐helper cell polarization is closely linked to the RANKL/OPG ratio in gingival tissues from chronic periodontitis patients.

Rab-interacting lysosomal protein (RILP) is a regulator of late stages of endocytosis. Recent work proved that depletion of RILP promotes migration of breast cancer cells in wound healing assay, whereas its overexpression influences re-arrangements of actin cytoskeleton. Here, we further characterized the role of RILP in cell migration by analyzing several aspects of this process. We showed that RILP is fundamental also for migration of lung cancer cells regulating cell velocity. RILP silencing did not affect Golgi apparatus nor microtubules reorientation during migration. However, both RILP over-expression and expression of its mutated form, RILP-C33, impair cell adhesion and spreading. In conclusion, our results demonstrate that RILP has important regulatory roles in cell motility affecting migration velocity but also in cell adhesion and cell spreading.

Although several studies have focused on allergic sensitization by dendritic cells, to date it is still open under which conditions these antigen‐presenting cells are able to induce an allergic immune response. Our study reveals that BMDCs pulsed with LPS‐free ovalbumine did not induce allergic disease. However, when BMDCs were activated with low‐dose LPS during pulsing with allergen, these cells expressed an inflammatory set of cytokines and co‐stimulatory molecules like CD86 and OX40L. Moreover, activated cells were able to prime mice for massive eosinophilic inflammation of the lung, airway hyper‐reactivity, IgE production and production of Th2 cytokines by lymphocytes. Blocking experiments showed that expression of OX40L is not involved in induction of Th2 response. Interestingly, BMDCs that were activated with high dose of LPS lose their Th2‐sensitizing capacity. Instead these cells induce a Th17 type immune response. We conclude that presentation of allergen by dendritic cells generated with GMCSF is not sufficient to lead to induction of allergic immune response. Further activation of BMDCs is required to prime mice for allergic immune response. In this study, we show that LPS is a suitable stimulus. However, when cells were activated with high dose LPS they tended to induce a Th17 response.

While the roles of glucose metabolism and tricarboxylic acid (TCA) cycle intermediates in immune regulation are well established, the contribution of fatty acid metabolism remains less well defined. In this review, we examine current knowledge on the immunomodulatory functions of fatty acid metabolism, with a particular focus on T‐cell biology. We discuss the catabolic, anabolic and signalling aspects of lipid metabolism and their influence on immune function. Short‐chain fatty acids modulate T‐cell epigenetics through histone acetylation, thereby impacting gene expression. Medium‐ and long‐chain fatty acids augment fatty acid oxidation (FAO), which supports the expansion and function of regulatory T‐cell populations. Very‐long‐chain polyunsaturated fatty acids, when cleaved from the membrane, serve as precursors for both pro‐inflammatory and pro‐resolving signalling molecules. Additionally, de novo fatty acid synthesis contributes to membrane biogenesis and alters acetyl‐CoA availability, linking lipid metabolism to epigenetic regulation. The mechanisms described above present promising opportunities to modulate inflammation through targeted therapies. In this review, we focus on emerging targets within fatty acid metabolism pathways that show potential for influencing inflammatory responses in translational models. Specifically, we review key transcription factors, metabolic enzymes and dietary interventions, while also addressing current limitations and challenges in translating these findings to clinical settings. Although studies in murine models have yielded encouraging results, substantial gaps remain—particularly in applying these metabolic strategies to human T‐cell biology. We conclude by emphasising the importance of validating these targets in ex vivo human models as a critical step towards future clinical intervention.

Natural killer (NK) cells, effector lymphocytes of the innate immunity, have been shown to be altered in several cancers, both at tissue and peripheral levels. We have shown that in Non-Small Cell Lung Cancer (NSCLC) and colon cancer, tumour associated circulating NK (TA-NK) and tumour infiltrating NK (TI-NK) exhibit pro-angiogenic phenotype/functions. However, there is still a lack of knowledge concerning the phenotype of peripheral blood (PB) NK (pNK) cells in prostate cancer (PCa). Here, we phenotypically and functionally characterized pNK from PCa patients (PCa TA-NKs) and investigated their interactions with endothelial cells and monocytes/macrophages. NK cell subset distribution in PB of PCa patients was investigated, by multicolor flow cytometry, for surface antigens expression. Protein arrays were performed to characterize the secretome on FACS-sorted pNK cells. Conditioned media (CM) from FACS-sorted PCa pTA-NKs were used to determine their ability to induce pro-inflammatory/pro-angiogenic phenotype/functions in endothelial cells, monocytes, and macrophages. CM from three different PCa (PC-3, DU-145, LNCaP) cell lines, were used to assess their effects on human NK cell polarization in vitro , by multicolor flow cytometry. We found that PCa pTA-NKs acquire the CD56 bright CD9 + CD49a + CXCR4 + phenotype, increased the expression of markers of exhaustion (PD-1, TIM-3) and are impaired in their degranulation capabilities. Similar effects were observed on healthy donor-derived pNK cells, exposed to conditioned media of three different PCa cell lines, together with increased production of pro-inflammatory chemokines/chemokine receptors CXCR4, CXCL8, CXCL12, reduced production of TNFα, IFNγ and Granzyme-B. PCa TA-NKs released factors able to support inflammatory angiogenesis in an in vitro model and increased the expression of CXCL8, ICAM-1, and VCAM-1 mRNA in endothelial cells. Secretome analysis revealed the ability of PCa TA-NKs to release pro-inflammatory cytokines/chemokines involved in monocyte recruitment and M2-like polarization. Finally, CMs from PCa pTA-NKs recruit THP-1 and peripheral blood CD14 + monocyte and polarize THP-1 and peripheral blood CD14 + monocyte-derived macrophage towards M2-like/TAM macrophages. Our results show that PCa pTA-NKs acquire properties related to the pro-inflammatory angiogenesis in endothelial cells, recruit monocytes and polarize macrophage to an M2-like type phenotype. Our data provides a rationale for a potential use of pNK profiling in PCa patients.

We consider a system of two nonlocal and nonlinear partial differential equations that describe some aspects of yeast cell-cell communication. We study local and global existence and uniqueness of solutions. We consider mild solutions and we perform bilinear and trilinear fixed point arguments in suitable functional spaces.

Accumulating evidence indicates that metabolism reprogramming is critically important to T cell differentiation, and manipulating metabolic pathways in T cells can shape their fate and function. During T cell differentiation, metabolism provides T cells with energy as well as precursors for various biological processes. Some key metabolic reactions, such as glycolysis, oxidative phosphorylation and fatty acid oxidation, are also considered to play important roles in T cell activation and differentiation. In this review, we will explain why cellular metabolism is important for the Th17/T-regulatory (Treg) cell balance and how metabolism reprogramming impacts this balance. Moreover, we will also discuss some important metabolic sensors, such as mammalian target of rapamycin, AMP-activated protein kinase, and some nuclear receptors. In addition, we will review specific small molecular compounds, which can shift the Th17/Treg cell balance and, therefore, have promising therapeutic roles. Finally, potential methods of manipulating Th17 cell metabolism for treating Th17-associated diseases will be discussed.

Background Investigating the pathophysiological mechanisms of early osteoarthritis (OA) is of utmost interest since this stage holds the strongest promise for therapeutic interventions. The aims of this study were to analyze if synovial inflammation is already present in early OA and to characterize the involved cell populations, by investigating synovial fluid (SF) and synovial membrane (SM) of early OA patients for the presence and polarization status of CD4 T cells. Methods A quantitative analysis of CD4 + T cell infiltration in SF and SM compared to peripheral blood (PB) was performed in patients with early stages of OA. We further investigated intracellular staining (ICS), surface marker, and chemokine receptor expression profiles of CD4 + T cells in SF, SM, and PB, as well as cytokine expression in native SF and PB. Matched samples of SF, SM, and PB were harvested from 40 patients with early OA at the time of surgery. Early OA was confirmed by independent surgeons intraoperatively. Samples were analyzed by flow cytometry for surface markers and cytokines, which are preferentially expressed by distinct T cell subsets (Th1, Th2, Th17, regulatory T cells). Furthermore, we analyzed native SF and PB supernatants using MACSPlex for multiple cytokine expression profiles. Results SF and SM showed a distinct infiltration of CD4 + T lymphocytes, with significantly increased expression of chemokine receptors CXCR3/CCR5, cytokine IFN-γ (preferentially expressed by Th1 cells), and CD161 (preferentially expressed by IL-17 producing Th17 cells) compared to PB. Furthermore, the percentage of CD4 + T cells polarized to Treg was significantly increased in SM compared to SF and PB. No significant differences were observed for CCR3 and CCR4 (preferentially expressed by Th2 cells), although IL-4 values were significantly higher in SM and SF compared to PB. Cytokine analysis showed comparable results between PB and SF, with only IL-6 being significantly increased in SF. Conclusions Early OA joints show already significant inflammation through CD4 + T cell infiltration, with predominant Th1 cell polarization. Inflammation seems to be driven by direct proinflammatory cell interaction. Cytokine signaling seems to be negligible at the site of inflammation in early OA, with only IL-6 being significantly increased in SF compared to PB.