Regulation Of Cell Function Research Articles

Autocrine TGF-β1 drives tissue-specific differentiation and function of resident NK cells.

Group 1 innate lymphoid cells (ILCs) encompass NK cells and ILC1s, which have non-redundant roles in host protection against pathogens and cancer. Despite their circulating nature, NK cells can establish residency in selected tissues during ontogeny, forming a distinct functional subset. The mechanisms that initiate, maintain, and regulate the conversion of NK cells into tissue-resident NK (trNK) cells are currently not well understood. Here, we identify autocrine transforming growth factor-β (TGF-β) as a cell-autonomous driver for NK cell tissue residency across multiple glandular tissues during development. Cell-intrinsic production of TGF-β was continuously required for the maintenance of trNK cells and synergized with Hobit to enhance cytotoxic function. Whereas autocrine TGF-β was redundant in tumors, our study revealed that NK cell-derived TGF-β allowed the expansion of cytotoxic trNK cells during local infection with murine cytomegalovirus (MCMV) and contributed to viral control in the salivary gland. Collectively, our findings reveal tissue-specific regulation of trNK cell differentiation and function by autocrine TGF-β1, which is relevant for antiviral immunity.

From brain to blood and back again: Linking chronic stress, myelopoiesis, and depression

In this issue of Cell Stem Cell, Mou etal. identified a brain-bone marrow axis reinforcing myelopoiesis and neuroinflammation during psychological stress, culminating in depression. The identification of this pathway provides insights into hematopoietic stem cell homeostasis and regulatory neuronal function with potentially significant implications for the treatment of stress-related disorders.

LncRNA H19 Promotes Angiogenesis in Mouse Pulmonary Artery Endothelial Cells by Regulating the HIF-1α/VEGF Signaling Pathway.

Persistent pulmonary hypertension of the newborn (PPHN) is a syndrome of acute respiratory failure characterized by systemic hypoxemia and elevated pulmonary arterial pressure, which leads to pathological changes in pulmonary vascular remodeling and endothelial cell function. Long non-coding RNA (lncRNA) H19 has been shown to be involved in the regulation of arterial endothelial cell function, but its regulatory role in PPHN is not fully understood. In the present study, mouse pulmonary artery endothelial cells (MPAECs) were cultured in a hypoxic conditions. Subsequently, the regulatory function of lncRNA H19 on MPAECs was explored by constructing adenoviruses knocking down and overexpressing lncRNA H19. The results revealed that the hypoxic conditions could induce the proliferation and migration of MPAECs, as well as the high expression of lncRNA H19 in MPAECs. Knockdown of lncRNA H19 expression in MPAECs reversed hypoxic environment-induced functional changes in endothelial cells, whereas overexpression of lncRNA H19 further enhanced the proliferation and migration of MPAECs. In addition, lncRNA H19 upregulated the hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway through sponge of miNA-20a-5p, which in turn promoted changes in endothelial cell function. LncRNA H19 may interfere with vascular remodeling in hypoxia-induced pulmonary hypertension by upregulating the expression of HIF-1α and VEGF in vascular endothelial cells.

Regulation of cochlear hair cell function by intracellular calcium stores.

Mammalian hearing depends on the dual mechanosensory and motor functions of cochlear hair cells. Both these functions may be regulated by Ca2+ release from intracellular stores. However, it is still unclear how exactly intracellular Ca2+ release may affect either hair cell mechano-electrical transduction (MET) or prestin-dependent electromotility in outer hair cells (OHCs). Here, we used photo-activatable (caged) compounds to generate fast increases of either Ca2+ or inositol-3-phosphate (IP3) in the cytosol of young postnatal rodent auditory hair cells, thereby stimulating either Ca2+- or IP3- induced releases of Ca2+ from intracellular stores. Fast Ca2+ imaging was used to monitor propagation of Ca2+ signals along the length of a hair cell. To access potential physiological role(s) of intracellular Ca2+ releases, we used whole cell patch clamp to record: i) OHC voltage-dependent capacitance, a known electrical correlate of prestin-based electromotility, and ii) MET currents evoked by stereocilia bundle deflections with fluid-jet. In the latter experiments, changes of mechanical stiffness of the hair bundles were also quantified from video recordings of stereocilia movements. Ca2+ uncaging at the OHC apex initiated Ca2+ wave propagating to the base of the cell with subsequent Ca2+ build-up there. Ca2+ uncaging at the OHC base generated long-lasting and apparently self-sustained Ca2+ responses, further confirming Ca2+-induced Ca2+ release in the OHC basal region. Photoactivated IP3 initiated a slow increase of cytosolic Ca2+ ([Ca2+] i ) throughout the whole OHC, confirming the presence of slow-activated IP3-gated Ca2+ stores in OHCs. Interestingly, Ca2+ uncaging produced no effects on OHC voltage-dependent capacitance. In an OHC, the rise of [Ca2+] i is known to decrease axial stiffness of the cell and may modulate the stiffness of mechanosensory stereocilia bundles. To separate these two phenomena, we explored the potential effects of intracellular Ca2+ release on mechanical properties of stereocilia bundles in cochlear inner hair cells (IHCs). Ca2+ uncaging at the apex of an IHC caused a long-lasting increase in mechanical stiffness of stereocilia bundle without any changes in the amplitude or deflection sensitivity of the MET current. We concluded that the most likely physiological role of IP3-gated Ca2+ release at the apex of the cell is the regulation of hair bundle stiffness. In contrast, Ca2+-induced Ca2+ release at the base of OHCs seems to regulate axial stiffness of the cells and its hyperpolarization in response to efferent stimuli, without direct effects on the OHC prestin-based membrane motors.

Apparent lncRNAs involvement in pathogenesis of endometriosis

Endometriosis is an estrogen-dependent, debilitating gynecologic disease impacting millions of women globally. One of the main characteristics of this benign condition is the presence of endometrial-like tissue outside the uterus, causing dysmenorrhea, chronic pelvic pain, and infertility. However, despite many reports on the origin and molecular pathogenesis of endometriosis, the etiology of this disease has not been fully explored yet. Recently, significant attention has been paid to long noncoding RNAs (lncRNAs). Numerous studies focused on exploring the association between lncRNAs and the progression of various human diseases. LncRNAs function as competing endogenous RNAs (ceRNAs) interacting with microRNAs as a “sponge” to regulate cell functions. According to multiple studies, lncRNAs seem to have the potential as markers for diagnosing, and monitoring progression and staging in endometriosis. In this review, we summarized the lncRNAs that were found to influence the pathogenesis of endometriosis. Furthermore, we tried to assess its potential in the process of endometriosis transition from benign through atypical forms, up to EAOC (Endometriosis Associated Ovarian Cancer).

Germline natural killer cell receptors modulating the T cell response.

In addition to their central role during innate responses, NK cells regulate adaptive immunity through various mechanisms. A wide array of innate receptors has been involved in the NK cell regulatory function. However, the clinical implications of these regulatory pathways are poorly understood. Here, we review the experimental evidence on the effects of NK cells on T cells and their positive and negative consequences for disease outcome during T cell responses in humans.

Targeted CRISPR regulation of ZNF865 enhances stem cell cartilage deposition, tissue maturation rates, and mechanical properties in engineered intervertebral discs

Cell and tissue engineering based approaches have garnered significant interest for treating intervertebral disc degeneration and associated low back pain due to the substantial limitations of currently available clinical treatments. Herein we present a clustered regularly interspaced short palindromic repeats (CRISPR)-guided gene modulation strategy to improve the therapeutic potential of cell and tissue engineering therapies for treating intervertebral disc disease. Recently, we discovered a zinc finger (ZNF) protein, ZNF865 (BLST), which is associated with no in-depth publications and has not been functionally characterized. Utilizing CRISPR-guided gene modulation, we show that ZNF865 regulates cell cycle progression and protein processing. As a result, regulating this gene acts as a primary titratable regulator of cell activity. We also demonstrate that targeted ZNF865 regulation can enhance protein production and fibrocartilage-like matrix deposition in human adipose-derived stem cells (hASCs). Furthermore, we demonstrate CRISPR-engineered hASCs ability to increase GAG and collagen II matrix deposition in human-size tissue-engineered discs by 8.5-fold and 88.6-fold, respectively, while not increasing collagen X expression compared to naive hASCs dosed with growth factors. With this increased tissue deposition, we observe significant improvements in compressive mechanical properties, generating a stiffer and more robust tissue. Overall, we present novel biology on ZNF865 and display the power of CRISPR-cell engineering to enhance strategies treating musculoskeletal disease. Statement of significanceThis work reports on a novel gene, ZNF865 (also known as BLST), that when regulated with CRISPRa, improves cartilagenous tissue deposition in human sized tissue engineering constructs. Producing tissue engineering constructs at human scale has proven difficult, and this strategy presents a broadly applicable tool to enhance a cells ability to produce tissue at these scales, as we saw an ∼8–88 fold increase in tissue deposition and significantly improved biomechanics in large tissue engineered intervertebral disc compared to traditional growth factor differentiation methods. Additionally, this work begins to elucidate the biology of this novel zinc finger protein, which appears to be critical in regulating cell function and activity.

Egfl6 promotes ovarian cancer progression by enhancing the immunosuppressive functions of tumor-associated myeloid cells.

Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with β3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cell migration and promotes their differentiation toward an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intratumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10, and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to anti-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of anti-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression colocalized with myeloid cell infiltration. scRNA-Seq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the oncoimmunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential therapeutic target to enhance immunotherapy in patients with OvCa.

Role of ADAM10/17-mediated Cleavage of LAG3 in the Impairment of Immunosuppression in Psoriasis

Despite extensive research on immune activation regulatory mechanisms, studies on immune suppression in psoriasis are limited. LAG3, a newly identified immune checkpoint, plays a crucial role in modulating immune responses and maintaining T regulatory (Treg) cell function. However, its involvement in psoriasis is unclear. We show that psoriasis is associated with reduced LAG3 expression in CD4 T cells and Treg cells. Further analysis revealed that the decline in LAG3 levels was linked to ADAM10/17-mediated proteolytic cleavage, which was upregulated in psoriasis. Clinical utilization of the IL-17A antagonist secukinumab, along with the in-vivo and in-vitro IL-17A-induced models, supported the potential of IL-17A to induce ADAM10/17 expression and trigger LAG3 cleavage. Through the Jurkat cell model, IL-17A was found to regulate ADAM10/17 expression by activating FOXM1. Additionally, treatment with the ADAM10/17 inhibitor GW280264X showed ameliorative effects on psoriasis-like mouse models and lipopolysaccharide-induced inflammation. Collectively, the findings of this study uncover the immune regulatory role of the ADAM10/17-LAG3 axis in psoriasis and highlight the therapeutic potential of targeting ADAM10/17 for psoriasis treatment.

Interplay Between the MicroRNA miR-152 and Quercetin in the Control of Ovarian Granulosa Cell Functions

In the present study, we examined the functional interrelationships between microRNAs and plant polyphenols in the regulation of ovarian cell functions. For this purpose, we compared the basic functions of porcine ovarian granulosa cells with or without transfection with miR-152 mimics that were cultured with or without quercetin. The expression levels of miR-152, cell viability, cell proliferation (accumulation of proliferating cell nuclear antigen, PCNA), apoptosis (accumulation of Bax) and the release of progesterone, estradiol, and insulin-like growth factor I (IGF-I) were analyzed by real-time quantitative polymerase chain reaction (RT‒qPCR), the Trypan blue exclusion test, quantitative immunocytochemistry, and enzyme-linked immunosorbent assays (ELISAs). Transfection of cells with miR-152 mimics increased miR-152 expression, reduced cell viability, proliferation, apoptosis, and estradiol output, and promoted the release of progesterone and IGF-I. Quercetin decreased all measured parameters. Moreover, quercetin promoted the effect of miR-152 on cell viability, apoptosis, and estradiol and mitigated the effect of miR-152 on cell proliferation and IGF-I output. For instance, miR-152 mimics promoted the effect of quercetin on cell viability, apoptosis, and estradiol but prevented the effect of quercetin on PCNA. These observations demonstrated the involvement of miR-152 and quercetin in the control of ovarian cell functions and their functional interrelationships, mainly synergism, in the regulation of these functions.

Protease activated receptor 2 deficiency retards progression of abdominal aortic aneurysms by modulating phenotypic transformation of vascular smooth muscle cells via ERK signaling

Abdominal aortic aneurysm (AAA) is characterized by localized structural deterioration of the aortic wall, leading to progressive dilatation and rupture. Protease activated receptor 2 (PAR2) dependent signaling has been implicated in the pathophysiology of atherosclerosis through the regulation of smooth muscle cell function. However, its role in AAA remains unclear. This study investigates the function and potential mechanism of PAR2 in AAA progression. Angiotensin II (Ang II) and β-aminopropionitrile (BAPN) were administered to wild type (WT) mice to induce AAA. Increased PAR2 expression was observed in the aneurysmal tissues of these mice and in Ang II-treated vascular smooth muscle cells (VSMCs). We demonstrated that PAR2 deficiency markedly inhibited aorta dilatation and vascular remodeling in the AAA model relative to WT mice. Immunohistochemical staining showed significant upregulation of contractile markers and a reduction in synthetic markers in PAR2 knockout mice. Consistent with in vivo results, PAR2 knockdown diminished the effects of Ang II on VSMCs phenotypic switching, resulting in reduced proliferation and migration. Conversely, a PAR2 agonist (SLIGRL) induced the opposite effect, which was partially mitigated by pretreatment with an extracellular signal-regulated kinase (ERK) inhibitor (PD98059). This study suggests that PAR2 deficiency restrains aortic expansion and mitigates adverse vascular remodeling in AAA models, mediated in part by the ERK signaling pathway, indicating that PAR2 could be a potential therapeutic target for mitigating AAA development or progression.

Mesenchymal stem cell transplant as an intervention to ameliorate disuse-induced muscle atrophy in a mouse model of simulated microgravity

BackgroundThe hindlimb unloaded (HU) mouse model exhibits disuse-induced muscle atrophy. However, effective interventions remain elusive. We investigated the therapeutic potential of mesenchymal stem cells (MSC) transplant on muscle decline in HU mice. MethodsWe divided 4-month-old male c57BL/6j mice into controls and HU mice treated with PBS as placebo (HU-PBS) or MSCs (HU-MSC; one million cells/100 μl PBS into gastrocnemius muscles once a week) for three weeks. We measured muscle mass, grip strength, and an unbiased transcriptome analysis of gastrocnemius muscles. ResultsMSC treatment prevented muscle atrophy and improved grip strength in HU mice. Transcriptome analysis revealed MSC-induced unique (557 genes) and differential (1214 genes) expressions of several genes compared to the HU-PBS group. GO and KEGG term analysis revealed an HU-induced downregulation of pathways associated with the regulation of contractile apparatus, neuromuscular junction, and satellite cell function, which were partly reversed with MSC treatment. Lastly, MSC treatment also upregulated the pathways controlling muscle differentiation and growth in the HU mice. ConclusionAltogether, we report the therapeutic potential of MSCs in treating disuse-induced muscle atrophy and weakness. Our study may help unravel novel molecular mechanisms involved in MSCs-induced muscle restoration.

SESN2 Ameliorates Dihydrotestosterone-induced Human Ovarian Granulosa Cell Damage by Activating AMPK/ULK1-mediated Mitophagy.

Sestrin 2 (SESN2) has been reported to participate in the regulation of granulosa cell function in ovarian tissues. However, the role of SESN2 in polycystic ovarian syndrome (PCOS) is still incompletely understood. Here, we investigated the functional role and mechanism of SESN2 in dihydrotestosterone (DHT)-induced granulosa cells. In this study, DHT was utilized to induce PCOS cell model and the AMP-activated protein kinase (AMPK) inhibitor Compound C (CC) was utilized to inhibit the AMPK pathway. qRT-PCR was performed to detect the expression of SESN2 in HGLS cells. Cell apoptosis was evaluated by flow cytometry. Oxidative stress was detected by DCFH-DA staining, superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) kits. The expression of SESN2, cell apoptosis, oxidative stress, mitophagy and AMPK/ULK1 signaling-related proteins were measured by western blot. The results showed that SESN2 was downregulated in DHT-induced granulosa cells. Overexpression of SESN2 inhibited the DHT-induced apoptosis and oxidative stress of HGLS cells. DHT induction aggravated HGLS cell apoptosis and oxidative stress. SESN2 overexpression inhibited the DHT-induced apoptosis and oxidative stress of HGLS cells. In addition, overexpression of SESN2 activated the AMPK/ULK1 signaling pathway and promoted mitophagy. Treatment of CC reversed the regulatory effect of SESN2 on mitophagy. CC also reversed the influences of SESN2 overexpression on apoptosis and oxidative stress in DHT-induced HGLS cells. Overall, SESN2 suppressed DHT-induced apoptosis and oxidative stress in PCOS through AMPK/ULK1-mediated mitophagy.

Treatment of Induced Mesenchymal Stem Cells in Ischemic Heart Diseases: Hypoxia

When traditional methods fall short in treating ischemic heart diseases caused by reduced blood flow to the heart due to narrowed coronary arteries, alternative solutions such as cellular therapies are thought. Mesenchymal stem cells (MSCs) are advantageous due to their ease of isolation, migration, and immunomodulatory properties. Preconditioning, which involves regulating cell functions through external stimuli, enhances the effectiveness of cellular therapy. Hypoxia, known as oxygen deprivation, is known to regulate cell survival, migration, and differentiation capabilities. This review explores the current state and future of hypoxia preconditioning in enhancing the therapeutic effects of stem cells.

Complement, Coagulation, and Fibrinolysis: The Role of the Endothelium and Its Glycocalyx Layer in Xenotransplantation.

In xenotransplantation, the vascular endothelium serves as the first point of contact between the recipient's blood and the transplanted donor organ. The loss of the endothelium's ability to control the plasma cascades plays a critical role in the dysregulation of the complement and coagulation systems, which greatly contribute to graft rejection and hinder long-term xenograft survival. Although it is known that an intact glycocalyx is a key feature of a resting endothelium that exhibits optimal anticoagulant and anti-inflammatory properties, the role of the endothelial glycocalyx in xenotransplantation is barely investigated so far. Here, we discuss the central role of endothelial cells and the sugar-rich endothelial glycocalyx in regulating the plasma cascades, and how the loss of these functions contributes to graft damage and rejection. We highlight the importance of preserving the regulatory functions of both endothelial cells and the glycocalyx as strategies to improve xenotransplantation outcomes.

Investigating the regulatory mechanism of glucose metabolism by ubiquitin-like protein MNSFβ.

Monoclonal nonspecific suppressor factor β (MNSFβ), a ubiquitously expressed member of the ubiquitin-like protein family, is associated with diverse cell regulatory functions. It has been implicated in glycolysis regulation and cell proliferation enhancement in the macrophage-like cell line Raw264.7. This study aims to show that HIF-1α regulates MNSFβ-mediated metabolic reprogramming. In Raw264.7 cells, MNSFβ siRNA increased the oxygen consumption rate and reactive oxygen species (ROS) production but decreased ATP levels. Cells with MNSFβ knockdown showed a markedly increased ATP reduction rate upon the addition of oligomycin, a mitochondrial ATP synthase inhibitor. In addition, MNSFβ siRNA decreased the expression levels of mRNA and protein of HIF-1α-a regulator of glucose metabolism. Evaluation of the effect of MNSFβ on glucose metabolism in murine peritoneal macrophages revealed no changes in lactate production, glucose consumption, or ROS production. MNSFβ affects both glycolysis and mitochondrial metabolism, suggesting HIF-1α involvement in the MNSFβ-regulated glucose metabolism in Raw264.7 cells.

The Role of Interleukin-24 and Downstream Pathways in Inflammatory and Autoimmune Diseases.

Inflammatory and autoimmune diseases are pathological immune disorders and pose significant public health challenges due to their impact on individuals and society. Cytokine dysregulation plays a critical role in the development of these disorders. Interleukin (IL)-24, a member of the IL-10 cytokine family, can be secreted by various cell types, including immune and non-immune cells. The downstream effects of IL-24 upon binding to its receptors can occur in dependence on, or independently of, the Janus kinase (JAK)/signal transducer and the activator of transcription (STAT) signaling pathway. IL-24 and its downstream pathways influence crucial processes such as cell differentiation, proliferation, apoptosis, and inflammation, with its role varying across different diseases. On the one hand, IL-24 can inhibit the activation of pathogenic cells and autoimmune responses in autoimmune ocular diseases; on the other hand, IL-24 has been also implicated in promoting tissue damage by fostering immune cell activation and infiltration in psoriasis and allergic diseases. It suggests that IL-24, as a multifunctional cytokine, has complex regulatory functions in immune cells and related diseases. In this paper, we summarize the current knowledge on IL-24's immunomodulatory actions and its involvement in inflammatory and autoimmune disorders. Such insights may pave the way for novel therapeutic strategies for these diseases.

Spatial dimension cues derived from fibrous scaffolds trigger mechanical activation to potentiate the paracrine and regenerative functions of MSCs via the FAK-PI3K/AKT axis

Secretomes from mesenchymal stem cells (MSCs) have significant therapeutic potential and could be the basis for future MSCs treatments. Innovative design of the topology of biomaterials, which mechanically regulate cell behavior and function, can tremendously improve the efficacy of stem cell therapy. However, how spatial dimension cues derived from specific topology command cell mechanotransduction to regulate the paracrine function of MSCs remains unknown. In this study, the three-dimensional (3D) fibrous constructs with box-like pores and precise strand spacing from 150 µm down to only 40 µm were manufactured using melt electrowriting (MEW), which were used to systematically investigate the spatial dimension cues-triggered mechanotransduction of adipose-derived mesenchymal stem cells (Ad-MSCs) and their impact on the paracrine and regeneration function of Ad-MSCs. The results demonstrated that spatial instructions from the 3D fibrous constructs could influence the spatial reorganization of the cytoskeleton, resulting in cell elongation and augmented immunomodulatory and angiogenic paracrine effects of Ad-MSCs, which was most pronounced at a minimum strand spacing of 40 µm. Besides, mechanical activation of the FAK-PI3K/AKT axis significantly enhanced the paracrine function of Ad-MSCs. In vivo experiments demonstrated that the Ad-MSCs trained using well-defined 3D fibrous constructs with a strand spacing of 40 µm significantly promoted skin regeneration via paracrine signals. In conclusion, this study provides a new horizon for deciphering space dimension insights into the interactional mechanisms of mechanotransduction in regulating cell function, which has inspired innovations in biomaterials for improving tissue regeneration. Statement of significanceThis study emphasized that designing cell-scale spatial dimension cues to command mechanical activation via the FAK-PI3K/AKT axis could significantly enhance the paracrine and regenerative functions of Ad-MSCs. Paracrine signals of Ad-MSCs triggered by mechanical activation promoted skin repair and regeneration via the immunomodulation and angiogenesis. The proposed mechanobiological signal transduction triggered by spatial dimensional cues, which potentiates the paracrine and regenerative functions of Ad-MSCs, is a promising engineering strategy and is expected to provide new inspirations for the development of biomaterials based on biophysical signals for cellular behavior modulation.

CCR2+TREM-1+ monocytes promote natural killer T cell dysfunction contributing towards HBV disease progression.

Natural killer T (NKT) cells are amongst the most important innate immune cells against hepatitis B virus (HBV) infection. Moreover, previous studies have shown that HBV infection induced TREM-1+ expression in monocyte and secretion of inflammatory cytokines. Thus, this prompted us to elucidate the role of TREM-1+ monocytes in regulating the function of iNKT cells. Ninety patients and 20 healthy participants were enrolled in the study. The percentage and phenotype of iNKT cells and TREM-1+ monocytes were measured in the peripheral blood of healthy controls (HC), patients with chronic HBV infection (CHB), HBV-related liver cirrhosis (LC), and HBV-related acute-on-chronic liver failure (ACLF) via flow cytometry. Moreover, co-culture experiments with iNKT cells and TREM-1 overexpressing THP-1 cells were performed to determine the role of TREM-1 in the regulation of NKT cell function. We observed that the percentage of iNKT cells and CD4-iNKT cells gradually decreased, whereas the percentage of CCR2+TREM-1+ monocytes increased with the progression of the disease. In addition, activation of the TREM-1 signaling pathway induced the secretion of inflammatory cytokines leading to pyroptosis of iNKT cells and secretion of IL-17 contributing towards disease progression. Therefore, this study suggests that blocking the activation of TREM-1 in monocytes could promote the elimination of HBV by inhibiting pyroptosis of iNKT cells and restoring their function. However, further studies are required to validate these results that would help in developing new treatment strategies for patients with HBV infections.

Eukaryotic cell size regulation and its implications for cellular function and dysfunction.

Depending on cell type, environmental inputs, and disease, the cells in the human body can have widely different sizes. In recent years, it has become clear that cell size is a major regulator of cell function. However, we are only beginning to understand how the optimization of cell function determines a given cell's optimal size. Here, we review currently known size control strategies of eukaryotic cells and the intricate link of cell size to intracellular biomolecular scaling, organelle homeostasis, and cell cycle progression. We detail the cell size-dependent regulation of early development and the impact of cell size on cell differentiation. Given the importance of cell size for normal cellular physiology, cell size control must account for changing environmental conditions. We describe how cells sense environmental stimuli, such as nutrient availability, and accordingly adapt their size by regulating cell growth and cell cycle progression. Moreover, we discuss the correlation of pathological states with misregulation of cell size and how for a long time this was considered a downstream consequence of cellular dysfunction. We review newer studies that reveal a reversed causality, with misregulated cell size leading to pathophysiological phenotypes such as senescence and aging. In summary, we highlight the important roles of cell size in cellular function and dysfunction, which could have major implications for both diagnostics and treatment in the clinic.