Cell Communication and Signaling最新文献

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the deposition of immune complexes (ICs) in various organs, especially the kidney, leading to lupus nephritis, one of the major and therapeutically challenging manifestations of SLE. Among the various cytokines induced in SLE, type I interferons (IFN-Is) play crucial roles in mediating immunopathogenesis, and anti-IFN-I treatment has been approved for SLE treatment. The uptake of ICs by macrophages results in macrophage activation, which initiates, triggers, and exaggerates immune responses in SLE. After observing the induction of an IFN-stimulated gene, LY6E, in monocytes from SLE patients, we demonstrated the colocalization of both LY6E and a macrophage marker in kidneys from pristane-induced lupus-prone mice and from patients with lupus nephritis. By studying mouse bone marrow-derived macrophages, we showed that LY6E regulated IFN-α- and IC-induced production and secretion of mature interleukin-1β (mIL-1β), foam cell formation and several mitochondria-associated mechanisms, such as the release of mitochondrial DNA (mtDNA) but not mitochondrial RNA (mtRNA) into the cytosol, the generation of mitochondrial reactive oxygen species (mtROS) and ROS, the activation of caspase 1, NLRP3, and the stimulator of interferon genes (STING) signaling pathway, and the activation of cytidine/uridine monophosphate kinase 2 (CMPK2), which were involved in LY6E-mediated immunomodulatory effects. In addition, synergistic effects of a combination of IL-1β and IFN-α and of IL-1β and ICs on the induction of the expression of IFN-stimulated genes were observed. In addition to revealing the proinflammatory roles and mechanisms of LY6E in macrophages, given that various subgroups of macrophages have been identified in the kidneys of patients with lupus nephritis, targeted treatment aimed at LY6E may be a potential therapeutic for lupus nephritis.

Background: In the course of tumor treatment, radiation therapy (RT) not only kills cancer cells, but also induces complex biological effects in non-malignant cells around cancer cells. These biological effects such as angiogenesis, changes in stromal composition and immune cell infiltration remodel the tumor microenvironment (TME). As one of the major components of the TME, Cancer‑associated fibroblasts (CAFs) are not only involved in tumorigenesis, progression, recurrence, and metastasis but also regulate the tumor-associated immune microenvironment. CAFs and tumor cells or immune cells have complex intercellular communication in the context of tumor radiation.

Main content: Different cellular precursors, spatial location differences, absence of specific markers, and advances in single-cell sequencing technology have gradually made the abundant heterogeneity of CAFs well known. Due to unique radioresistance properties, CAFs can survive under high doses of ionizing radiation. However, radiation can induce phenotypic and functional changes in CAFs and further act on tumor cells and immune cells to promote or inhibit tumor progression. To date, the effect of RT on CAFs and the effect of irradiated CAFs on tumor progression and TME are still not well defined.

Conclusion: In this review, we review the origin, phenotypic, and functional heterogeneity of CAFs and describe the effects of RT on CAFs, focusing on the mutual crosstalk between CAFs and tumor or immune cells after radiation. We also discuss emerging strategies for targeted CAFs therapy.

Background: Immunotherapy has significantly improved outcomes for cancer patients; however, its clinical benefits vary among patients and its efficacy across breast cancer subtypes remains unclear. To enhance immunotherapy efficacy, it is important to gain more insight into tumor-intrinsic immunomodulatory factors that could serve as therapeutic targets. We previously identified Lactate Dehydrogenase C (LDHC) as a promising anti-cancer target due to its role in regulating cancer cell genomic integrity. In this study, we investigated the effects of tumor LDHC expression on immune responses.

Methods: TIMER AND TIDE deconvolution methods were used to investigate the relationship between tumor LDHC expression, immune cell infiltration and T cell dysfunction. Multiplex cytokine assays and flow cytometry were used to assess the effect of LDHC knockdown on the secretion of inflammatory molecules and expression of immune checkpoint molecules in breast cancer cells and cancer cell-immune cell co-cultures. T cell activity was determined by IFN-γ ELISPot assays and 7-AAD flow cytometry.

Results: TIMER and TIDE analyses revealed that tumor LDHC expression is associated with T cell dysfunction in breast cancer and poorer post-immunotherapy survival in melanoma. Silencing LDHC in breast cancer cell lines (MDA-MB-468, BT-549, HCC-1954) enhanced early T cell activation and cytolytic activity. To gain a better understanding of the underlying mechanisms, comparative analysis of the effects of LDHC knockdown in cancer cell monocultures and co-cultures was conducted. Following LDHC knockdown, we observed an increase in the secretion of tumor-derived pro-inflammatory cytokines (IFN-γ, GM-CSF, MCP-1, CXCL1), a decrease in the soluble levels of tumor-derived immunosuppressive factors (IL-6, Gal-9) and reduced tumor cell surface PD-L1 expression. In direct co-cultures, LDHC knockdown reduced the levels of pro-tumorigenic cytokines (IL-1β, IL-4 and IL-6) and increased the secretion of the chemokine CXCL1. In addition, the number of CD8 + T cells expressing PD-1 and CTLA-4 and the cell surface expression of CTLA-4, TIGIT, TIM3, and VISTA were reduced.

Conclusions: Our findings suggest that targeting LDHC could enhance anti-tumor immune responses by modulating cytokine and chemokine secretion in addition to impairing immune checkpoint signaling. Further studies are required to elucidate the molecular mechanisms by which LDHC modulates immune responses in breast cancer.

Background: Sleep disorders occur frequently among patients with Parkinson's disease (PD). Neurotransmitters and neurosteroids are known to be involved in various neurophysiological processes, including sleep development. We aimed to assess the associations of peripheral neurotransmitter and neurosteroid levels with various sleep disorders in early-stage PD.

Methods: Fifty-nine patients with early-stage PD and 30 healthy controls were enrolled. Demographic and clinical data were collected, and sleep conditions were comprehensively assessed with clinical questionnaires and polysomnography. Blood samples were obtained from all participants at 1:00 AM and 9:00 AM. The concentrations of plasma neurotransmitters and neurohormones were detected via high-performance liquid chromatography tandem mass spectrometry.

Results: Sleep disorders were common nonmotor symptoms (81.4%) and coexisted in approximately half of the patients. Dysautonomia was significantly associated with the presence of multiple sleep disorders. RBD was associated with dysautonomia and was negatively correlated with the plasma melatonin concentration at 1:00 AM (r = - 0.40, p = 0.002) in early-stage PD patients. The RLS group had higher PSQI scores, and RLS was negatively associated with the 5-hydroxytryptamine levels (r = - 0.40, p = 0.002) at 1:00 AM and glutamine levels (r = - 0.39, p = 0.002) at 9:00 AM. SDB was associated with cognitive impairment, a greater body mass index, and lower plasma acetylcholine concentrations at 1:00 AM.

Conclusion: Combined sleep disturbances are common in early-stage PD. Dysautonomia is closely related to various sleep disorders, including RBD, EDS, and insomnia. Changes in peripheral neurotransmitter and neurohormone levels may be involved in the development of sleep disorders.

Protein quality control (PQC) plays a vital role in maintaining normal heart function, as cardiomyocytes are relatively sensitive to misfolded or damaged proteins, which tend to accumulate under pathological conditions. Ubiquitin-specific protease (USP) is the largest deubiquitinating enzyme family and a key component of the ubiquitin proteasome system (UPS), which is a non-lysosomal protein degradation machinery to mediate PQC in cells. USPs regulate the stability or activity of the target proteins that involve intracellular signaling, transcriptional control of inflammation, antioxidation, and cell growth. Recent studies demonstrate that the USPs can regulate fibrosis, lipid metabolism, glucose homeostasis, hypertrophic response, post-ischemic recovery and cell death such as apoptosis and ferroptosis in cardiomyocytes. Since myocardial cell loss is an important component of cardiomyopathy, therefore, these findings suggest that the UPSs play emerging roles in cardiomyopathy. This review briefly summarizes recent literature on the regulatory roles of USPs in the occurrence and development of cardiomyopathy, giving us new insights into the molecular mechanisms of USPs in different cardiomyopathy and potential preventive strategies for cardiomyopathy.

Background: Keloid is a typical skin fibrotic disease with unclear mechanisms and limited therapeutic options. Fibroblast-induced fibrogenesis is a crucial cause of KD. However, the types of cells involved in fibroblast fibrogenesis in KD and the specific mechanisms are unclear. This study aimed to investigate the role of melanocyte-secreted melanin in promoting fibroblast fibrogenesis and its mechanism and to evaluate the potential therapeutic effect of intervening melanin in treating keloid.

Methods: The activity of pigmentation-related pathways in KD melanocytes was examined using single-cell RNA-sequence (scRNA-seq) analysis. Masson-Fontana staining or isolated melanin quantification detected the melanin levels and distribution in the skin and cells. Collagen deposition, wounding healing, and proliferation analysis were employed to integratively assess fibroblast fibrogenesis. After melanin treatment, bulk-seq identified fibroblasts' differentially expressed genes (DEGs). The iron levels were detected by Perl's staining or isolated iron quantification. Cell viability, LipidROS, and malondialdehyde assay accessed the ferroptosis levels. The therapeutic potential of ML329 was evaluated in keloid-bearing mice.

Results: We found the enriched skin pigmentation-related pathways in the melanocytes of keloid by single-cell RNA-sequence (scRNA-seq) analysis. We further validated increased melanin levels in keloid patients. Additionally, melanin positively correlated with the Keloid Area and Severity Index in keloid. Furthermore, melanocyte-secreted melanin significantly promoted fibroblast proliferation, migration, and collagen synthesis. Mechanically, melanin increased basal cell permeability and inflammation to facilitate its transfer to the dermis, where it further activated fibroblasts by evoking iron overload and ferroptosis resistance. Consistently, iron overload and ferroptosis resistance were validated in primary fibroblasts and skin tissues of keloid patients. Inhibition of iron overload and ferroptosis resistance effectively diminish melanin-induced fibrogenesis. Interestingly, melanin induced iron overload and ferroptosis resistance in melanocytes in an autocrine manner and further stimulated keratinocytes to take up melanin to deepen skin color by upregulating the F2R-like trypsin receptor 1 (F2RL1). In vivo, the delivery of ML329, a microphthalmia-associated transcription factor (MITF) inhibitor, could suppress melanogenesis and alleviate keloid in human keloid-bearing nude mice. Meanwhile, ML329 decreased the iron content and restored the sensitivities of ferroptosis.

Conclusion: Collectively, melanin-lowing strategies may appear as a potential new therapeutic target for keloid.

The LPS-TLR4 immune response is a critical mechanism in the body's defense against Gram-negative bacterial infections, yet its dysregulation can lead to severe inflammatory diseases. Lipopolysaccharide (LPS), a pivotal pathogen-associated molecular pattern (PAMP) on the surface of gram-negative bacteria, is recognized by Toll-like receptor 4 (TLR4), initiating a complex cascade of immune responses. This review delves into the intricate molecular structures and protein-protein interactions that underpin the LPS-TLR4 signaling pathway, offering a comprehensive analysis of both extracellular recognition and intracellular signal transduction. We explore the roles of key molecules such as LBP, CD14, MD-2, and TLR4 in the initial recognition of LPS, followed by the downstream signaling pathways mediated by MyD88-dependent and MyD88-independent mechanisms. The MyD88-dependent pathway primarily activates NF-κB and AP-1, leading to macrophage M1 polarization and the release of pro-inflammatory cytokines, while the MyD88-independent pathway triggers IRF activation and type-I interferon production. By elucidating the structural basis and functional interactions of these signaling molecules, this review not only enhances our understanding of the LPS-TLR4 immune response but also highlights its implications in both infectious and non-infectious diseases. Our findings underscore the potential of targeting this pathway for therapeutic interventions, offering new avenues for the treatment of inflammatory and immune-related disorders.

A dysregulated inflammatory response and inflammation-associated cell death are central features of renal ischemia-reperfusion injury (IRI). PANoptosis, is a recently recognized form of inflammatory programmed cell death characterized by key features of pyroptosis, apoptosis and necroptosis; however, the specific involvement of PANoptosis in renal IRI remains unknown. By using neutrophil extracellular trap (NETs)-depleted Pad4^-/- mice, we found that NETs are essential for exacerbating tissue injury in renal IRI. Single-cell RNA sequencing (scRNA-seq) revealed that IRI promoted PANoptosis signalling in proximal tubular epithelial cells (PTs), whereas PAD4 knockout inhibited PANoptosis signalling. PTs expressed mainly RIPK1-PANoptosomes, which executed NET-induced PANoptosis in PTs in renal IRI model mice. Mechanistically, NET-derived double-stranded RNA (dsRNA) promoted PANoptosis in PTs, and PT-expressed TLR3 was responsible for the sensing the extracellular dsRNA. Treating mice with chemical inhibitors of the dsRNA/TLR3 complex suppressed PANoptosis and alleviated tissue injury in renal IRI. Together, the results of this study reveal a mechanism by which the NET-dsRNA-TLR3 axis aggravates PT cell PANoptosis in renal IRI.

Caveolin-1 (CAV1) is a membrane protein that promotes migration, invasion and metastasis of cancer cells when phosphorylated on tyrosine-14 (Y14) by a cell intrinsic mechanism involving the activation of a novel Rab5-Rac1 signaling axis. Moreover, CAV1 expressed in aggressive cancer cells is included into extracellular vesicles (EVs) and such EVs increase the metastatic potential of recipient lower grade cancer cells. However, the relevance of CAV1 Y14 phosphorylation in these extrinsic EV-stimulated events remained to be determined. Here we used B16F10 mouse melanoma cells over-expressing wild-type CAV1, phospho-mimetic CAV1(Y14E) or phospho-null CAV1(Y14F) as models to determine how the EV protein content was affected by Y14 phosphorylation and how these EVs modulated the metastatic potential of recipient B16F10 cells lacking CAV1. EVs from B16F10 cells over-expressing wild-type and CAV1(Y14/E) contain CAV1, and other proteins linked to signaling pathways associated with cell adhesion and migration. CAV1 inclusion in EVs was reduced by the Y14F mutation and global protein composition was also significantly different. Moreover, CAV1 wild-type and CAV1(Y14E) EVs promoted migration, as well as invasion of cells lacking CAV1 [B16F10(Mock) cells]. In addition, β3 integrin was transferred via CAV1(Y14E) EVs to B16F10 (Mock) cells, and treatment with such EVs promoted metastasis of recipient B16F10(Mock) cells. Finally, CAV1(Y14E) EV-enhanced migration, invasion and metastasis of recipient cells was blocked by anti-αVβ3 antibodies. In conclusion, CAV1 phosphorylated on Y14 not only intrinsically promotes migration, invasion and metastasis of cells expressing the protein (in cis), but also favors the inclusion of CAV1 into EVs, as well as the extrinsic acquisition of malignant traits in recipient cells, through integrin transfer (in trans).

Background: Allergic asthma is a chronic airway disease characterized by an allergic response and altered immune tolerance. CD4⁺ tissue-resident memory T (TRM) cells are crucial in the chronic and relapsing pathogenesis of asthma. Furthermore, promyelocytic leukemia zinc finger (PLZF) is an essential transcription factor involved in asthmatic tolerance and has been implicated in the regulation of CD4⁺CD44⁺ memory T cells. However, the role of CD4⁺ TRM cells in asthmatic tolerance, as well as their potential modulation by PLZF, remain unclear. Therefore, in the current study, we explore the role of CD4⁺ TRM cells in asthmatic immune tolerance and as well as the regulatory role of PLZF in this process.

Methods: To elucidate the role of CD4⁺ TRM cells in immune tolerance, asthma memory mouse models were treated with the immunomodulator FTY720. Subsequently, CD4⁺ T cells were isolated from the lungs and spleens and transferred to oral tolerance mouse models. To explore the regulation of PLZF in CD4⁺ TRM cells, asthma and oral tolerance were established in Zbtb16^flox/flox CD4^Cre and wild-type mice. Flow cytometry, histological analysis, and cytokine measurements were performed to characterize the immune response. The regulatory activity of PLZF on CD4⁺ TRM cells was analyzed through quantitative proteomics and verified in vitro and vivo.

Results: The CD4⁺ TRM cell proportion positively correlated with the pathological phenotypes and molecular characteristics of asthma. Adoptive transfer of CD4⁺ TRM cells induced asthmatic phenotypes. This suggested that CD4⁺ TRM cells contributed to the pathogenesis of asthma. Conditional knockout of PLZF substantially reduced the proportion of CD4⁺ TRM cells, relieved asthmatic symptoms, and suppressed the interleukin (IL)-15/IL-15Rα signaling pathway. Furthermore, exposure to the IL-15Rα agonist restored asthma-related Th2 inflammation, accompanied by a markedly increased proportion of CD4⁺ TRM cells. Meanwhile, IL-15 and ovalbumin(OVA)-primed Beas2b supernatant co-stimulation in vitro enhanced the differentiation of pulmonary PLZF-expressing CD4⁺ T cells into CD4⁺ TRM cells.  CONCLUSIONS: This study identified CD4⁺ TRM cells as key mediators of immune tolerance in asthma. This process is regulated by the transcription factor PLZF in CD4⁺ T cells through IL-15/IL-15Rα signaling. Thus, targeting PLZF or the IL-15/IL-15Rα pathway may represent a promising therapeutic strategy for treating asthma.