Immunopharmacology and Immunotoxicology最新文献

Background: Chronic obstructive pulmonary disease (COPD) has a high fatality rate and poses a great threat to human health. Astragaloside IV (AS-IV) is proven to attenuate cigarette smoke (CS)-induced pulmonary inflammation, based on which this research focuses on the mechanism of AS-IV in COPD.

Methods: To evaluate the effects of AS-IV, CD4⁺ T cells received different concentrations of AS-IV. CD4⁺ T cell viability, T helper 17 (Th17)/regulatory T (Treg) markers and CXCR4 expressions in CD4⁺ T cells or spleen/lung tissues were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, quantitative real-time polymerase chain reaction and Western blot. The proportions of Treg and Th17 cells were assessed by flow cytometry. Enzyme-linked immune sorbent assay was employed to determine cytokine contents in serum and lung tissues.

Results: AS-IV with concentration exceeding 40 µM inhibited CD4⁺ T cell viability. In vitro, AS-IV suppressed the expressions of CXCR4, retinoid-related orphan receptor γt (RORγt), and interleukin (IL)-17A as well as Th17 cells but promoted the expressions of forkhead box p3 (Foxp3) and IL-10 as well as Treg cells, while CXCR4 overexpression reversed the effects of AS-IV. In vivo, AS-IV alleviated COPD, and CS-induced Th17/Treg imbalance in mice and reduced CS-induced down-regulation of IL-10 in serum and lung tissues and Foxp3 and up-regulation of IL-1β, tumor necrosis factor alpha (TNF-α), IL-6, and IL-17A in serum and lung tissues and RORγt. AS-IV mitigated CS-induced CXCR4 up-regulation. Above effects of AS-IV on mice were offset by CXCR4 overexpression.

Conclusions: AS-IV restores Th17/Treg balance via impeding CXCR4 to ameliorate COPD.

Neuromuscular associated respiratory failure is a rare toxicity of immunotherapy for malignant tumors. In most cases, it may overlap with the symptoms of the primary disease or myocarditis, myositis and myasthenia gravis, resulting in difficult etiological diagnosis. Early detection and optimal treatment are still topics that need attention. Here, a case of 51-year-old male lung cancer patient with sintilimab-associated myasthenia gravis, myositis, and myocarditis overlap syndrome involving the diaphragm who developed severe type II respiratory failure was reported. After high-dose methylprednisolone, immunoglobulin and pyridostigmine intravenous injection with non-invasive positive pressure ventilation, the patient's symptoms improved significantly and was discharged. One year later, the patient received immunotherapy again due to tumor progression. After 53 days, he developed dyspnea again. Chest X-ray demonstrated marked elevation of the diaphragm, and the electromyogram demonstrated dysfunction of diaphragm. With rapid diagnosis and timely treatment, the patient was finally discharged safely. A comprehensive search of PubMed, EMBASE was performed to identify all previously reported cases of immune checkpoint inhibitors-associated respiratory failure. The potential mechanisms of respiratory failure caused by ICI-associated diaphragmatic dysfunction may be related to T cell-mediated immune disturbances and we proposed possible diagnostic processes. For patients with unexplained respiratory failure who are receiving immunotherapy, standardized diagnostic strategies should be implemented immediately on admission before deciding whether to conduct a more invasive diagnostic procedure or empirical treatment.

Objective: Treatment with TNF-α inhibitors improve psoriasis with minimize/minor neutrophils infiltration and CXCL-1/8 expression in psoriatic lesions. However, the fine mechanism of TNF-α initiating psoriatic inflammation by tuning keratinocytes is unclear. Our previous research identified the deficiency of intracellular galectin-3 was sufficient to promote psoriasis inflammation characterized by neutrophil accumulation. This study aims to investigate whether TNF-α participated in psoriasis development through dysregulating galectin-3 expression.

Methods: mRNA levels were assessed through quantitative real-time PCR. Flow cytometry was used to detect cell cycle/apoptosis. Western blot was used to evaluate the activation of the NF-κB signaling pathway. HE staining and immunochemistry were used to detect epidermal thickness and MPO expression, respectively. Specific small interfering RNA (siRNA) was used to knock down hsa-miR-27a-3p while plasmids transfection was used to overexpress galectin-3. Further, the multiMiR R package was utilized to predict microRNA-target interaction.

Results and discussion: We found that TNF-α stimulation altered cell proliferation and differentiation and promoted the production of psoriasis-related inflammatory mediators along with the inhibition of galectin-3 expression in keratinocytes. Supplement of galectin-3 could counteract the rise of CXCL-1/8 but not the other phenotypes of keratinocytes induced by TNF-α. Mechanistically, inhibition of the NF-κB signaling pathway could counteract the decrease of galectin-3 and the increase of hsa-miR-27a-3p expression whereas silence of hsa-miR-27a-3p could counteract the decrease of galectin-3 expression induced by TNF-α treatment in keratinocytes. Intradermal injection of murine anti-CXCL-2 antibody greatly alleviated imiquimod-induced psoriasis-like dermatitis.

Conclusion: TNF-α initiates psoriatic inflammation by increasing CXCL-1/8 in keratinocytes mediated by the axis of NF-κB-hsa-miR-27a-3p-galectin-3 pathway.

Background: Multiple targets of chimeric antigen receptor T cells (CAR-T cells) are shared expressed by tumor cells and T cells, these self-antigens may stimulate CAR-T cells continuously during the expansion. Persistent exposure to antigens is considered to cause metabolic reprogramming of T cells and the metabolic profiling is critical in determining the cell fate and effector function of CAR-T cells. However, whether the stimulation of self-antigens during CAR-T cell generation could remodel the metabolic profiling is unclear. In this study, we aim to investigate the metabolic characteristics of CD26 CAR-T cells, which expressed CD26 antigens themselves.

Methods: The mitochondrial biogenesis of CD26 and CD19 CAR-T cells during expansion was evaluated by the mitochondrial content, mitochondrial DNA copy numbers and genes involved in mitochondrial regulation. The metabolic profiling was investigated by the ATP production, mitochondrial quality and the expression of metabolism-related genes. Furthermore, we assessed the phenotypes of CAR-T cells through memory-related markers.

Results: We reported that CD26 CAR-T cells had elevated mitochondrial biogenesis, ATP production and oxidative phosphorylation at early expansion stage. However, the mitochondrial biogenesis, mitochondrial quality, oxidative phosphorylation and glycolytic activity were all weakened at later expansion stage. On the contrary, CD19 CAR-T cells did not exhibit such characteristics.

Conclusion: CD26 CAR-T cells showed distinctive metabolic profiling during expansion that was extremely unfavorable to cell persistence and function. These findings may provide new insights for the optimization of CD26 CAR-T cells in terms of metabolism.

Objective: This study aimed to evaluate the clinical effects and safety of immune checkpoint inhibitors (ICIs) combined with anti-VEGF therapy for the treatment of unresectable or advanced liver cancer.

Method: Related databases were searched from inception to December 2022 to identify randomized controlled studies and clinical trials that evaluated the combination of ICIs and anti-VEGF therapy for the treatment of unresectable liver cancer. The outcome index was extracted and analyzed by RevMan5.4.ResultsA total of 8 clinical trials were included. In terms of efficacy, the intervention group had longer OS and PFS for unresectable or advanced liver cancer than the control group. In terms of safety, (1) Adverse events of all grades showed that the combination treatment led to significantly higher risks of urinary system disorders, cardiovascular system disorder, blood system disorders and liver dysfunction than the control treatment. Compared with monotherapy, the combination treatment led to lower risks of gastrointestinal disorders. (2) Adverse events above grade 3 showed that, compared with the control treatment, the combination treatment led to significantly higher risks of urinary system disorders, blood systeam disorders, cardiovascular system disorders and liver dysfunction. Additionally, compared with monotherapy, the combination treatment led to significantly lower risks of gastrointestinal disorders.

Conclusions: ICIs combined with anti-VEGF therapy exerts significant clinical effects in patients with unresectable or advanced liver cancer, can prolong the survival of these patients and can improve their quality of life. However, clinical attention should be given to the occurrence of adverse reactions.

Context: Immune checkpoint inhibitors have advanced immunotherapy for melanoma patients.Objective: This study evaluates efficacy and safety of ipilimumab and nivolumab combination (IN) for melanoma brain metastases (MBM) patients.

Materials and methods: Literature search was conducted in electronic databases and studies were included if they reported efficacy and safety of IN in MBM patients or prognostic information related to brain metastases. Outcomes evaluated were objective response rate (ORR), complete remission/stable disease/progressive disease rates, progression-free survival (PFS), overall survival (OS), incidence rates of adverse events, and hazard ratios of disease progression or mortality between IN-treated patients with and without brain metastasis.

Results: Intracranial ORR was higher in IN-treated MBM patients than with control therapies (nivolumab or ipilimumab plus fotemustine). IN treatment led to longer PFS and OS in than control treatments. Five-year OS of IN-treated MBM patients was up to 51% compared to 34% for nivolumab. Outcomes were better for treatment naïve and asymptomatic patients. Whereas many studies reported significantly higher mortality or progression risk with IN treatment in MBM patients compared to non-MBM melanoma patients, many others did not find this risk significant. Incidence of grade 3/4 adverse events in IN-treated MBM patients was: diarrhea or colitis (16%), hepatitis (15%), rash (8%), increased alanine transaminase (8%), increased aspartate aminotransferase (7%), increased lipase (6%), increased amylase (4%), fatigue (3%), hypophysitis (2%), pneumonitis (2%), headache (2%), nausea or vomiting (1%), and neutropenia (1%).

Conclusion: IN is an efficacious and safer treatment option for MBM patients, especially for asymptomatic and treatment naïve patients.

Objective: Toll-like receptor 4 (TLR4) is crucial in induction of innate immune response through recognition of invading pathogens or endogenous alarming molecules. Ligand-triggered dimerization of TLR4 is essential for the activation of NF-κB and IRF3 through MyD88- or TRIF-dependent pathways. Saquinavir (SQV), an FDA-approved HIV protease inhibitor, has been shown to attenuate the activation of NF-κB induced by HMGB1 by blocking TLR4-MyD88 association in proteasome independent pathway. This study aims to define whether SQV is an HMGB1-specific and MyD88-dependent TLR4 signaling inhibitor and which precise signaling element of TLR4 is targeted by SQV.

Materials and methods: PMA differentiated human THP-1 macrophages or reconstituted HEK293 cells were pretreated with SQV before stimulated by different TLR agonists. TNF-α level was evaluated through ELISA assay. NF-κB activation was analyzed using NF-κB SEAP reporting system. The levels of MyD88/TRIF pathways-related factors were examined by immunoblot. TLR4 endocytosis was assessed by immunocytochemistry. TLR4 dimerization was determined using immunoprecipitation between different tagged TLR4 and an in silico molecular docking experiment was performed to explore the possible binding site of SQV on its target.

Results: Our data showed that SQV suppresses both MyD88- and TRIF-dependent pathways in response to lipopolysaccharide (LPS), a critical sepsis inducer and TLR4 agonist, leading to downregulation of NF-κB and IRF3. SQV did not suppress MyD88-dependent pathway triggered by TLR1/2 agonist Pam3csk4. In the only TRIF-dependent pathway, SQV did not alleviate IRF3 phosphorylation induced by TLR3 agonist Poly(I:C). Furthermore, dimerization of TLR4 following LPS or HMGB1 stimulation was decreased by SQV.

Conclusion: We concluded that TLR4 receptor complex is one of the mammalian targets of SQV, and TLR4-mediated immune responses and consequent risk for uncontrolled inflammation could be modulated by FDA-approved drug SQV.

Objective: Breast cancer (BC) causes cancer-related death in women. Sufentanil is used for cancer pain and postoperative analgesia. This study aimed to explore the role of sufentanil in BC.

Methods: BC cells were treated with sufentanil, and cell viability was evaluated using the cell counting kit-8 (CCK-8) assay. Biological behaviors were analyzed using EDU assay, flow cytometry, transwell assay, western blotting, and ELISA. The levels of NF-κB pathway-related factors were examined using western blotting. A xenograft tumor model was established to assess the effects of sufentanil on tumor growth in vivo.

Results: Sufentanil at the concentration of 20, 40, 80, and 160 nM suppressed cell viability (IC50 = 39.84 in MDA-MB-231 cells, and IC50 = 47.46 in BT549 cells). Sufentanil inhibited the proliferation, invasion, epithelial-mesenchymal transition (EMT), and inflammation, but induced apoptosis of BC cells. Mechanically, sufentanil suppressed the activation of the NF-κB pathway. Rescue experiments showed that RANKL (NF-κB receptor agonist) abrogated the effects induced by sufentanil. Moreover, sufentanil inhibited tumor growth, inflammatory response, but promoted apoptosis via the NF-κB pathway in vivo.

Conclusions: Sufentanil decelerated the progression of BC by regulating the NF-κB pathway, suggesting sufentanil may be used in BC therapy.

Context and objective: The emerging pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has imposed significant mortality and morbidity on the world. An appropriate immune response is necessary to inhibit SARS-CoV-2 spread throughout the body.

Results: During the early stages of infection, the pathway of stimulators of interferon genes (STING), known as the cGAS-STING pathway, has a significant role in the induction of the antiviral immune response by regulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Interferon regulatory factor 3 (IRF3), two key pathways responsible for proinflammatory cytokines and type I IFN secretion, respectively.

Discussion: During the late stages of COVID-19, the uncontrolled inflammatory responses, also known as cytokine storm, lead to the progression of the disease and poor prognosis. Hyperactivity of STING, leading to elevated titers of proinflammatory cytokines, including Interleukin-I (IL-1), IL-4, IL-6, IL-18, and tissue necrosis factor-α (TNF-α), is considered one of the primary mechanisms contributing to the cytokine storm in COVID-19.

Conclusion: Exploring the underlying molecular processes involved in dysregulated inflammation can bring up novel anti-COVID-19 therapeutic options. In this article, we aim to discuss the role and current studies targeting the cGAS/STING signaling pathway in both early and late stages of COVID-19 and COVID-19-related complications and the therapeutic potential of STING agonists/antagonists. Furthermore, STING agonists have been discussed as a vaccine adjuvant to induce a potent and persistent immune response.