Control of adaptive immune responses by Staphylococcus aureus through IL-10, PD-L1, and TLR2.
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ABSTRACT:
SUBMITTER: Wang J
PROVIDER: S-EPMC3428601 | biostudies-other | 2012
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Patient interleukin (IL)-1? and IL-10 responses early in Staphylococcus aureus bacteremia (SaB) are associated with bacteremia duration and mortality. We hypothesized that these responses vary depending on antimicrobial therapy, with particular interest in whether the superiority of ?-lactams links to key cytokine pathways. METHODS:Three medical centers included 59 patients with SaB (47 methicillin-resistant S. aureus [MRSA], 12 methicillin-sensitive S. aureus [MSSA]) from 2015-2017. In the first 48 hours, patients were treated with either a ?-lactam (n = 24), including oxacillin, cefazolin, or ceftaroline, or a glyco-/lipopeptide (n = 35), that is, vancomycin or daptomycin. Patient sera from days 1, 3, and 7 were assayed for IL-1? and IL-10 by enzyme-linked immunosorbent assay and compared using the Mann-Whitney U test. RESULTS:On presentation, IL-10 was elevated in mortality (P = .008) and persistent bacteremia (P = .034), while no difference occurred in IL-1?. Regarding treatment groups, IL-1? and IL-10 were similar prior to receiving antibiotic. Patients treated with ?-lactam had higher IL-1? on days 3 (median +5.6 pg/mL; P = .007) and 7 (+10.9 pg/mL; P = .016). Ex vivo, addition of the IL-1 receptor antagonist anakinra to whole blood reduced staphylococcal killing, supporting an IL-1? functional significance in SaB clearance. ?-lactam-treated patients had sharper declines in IL-10 than vancomycin or daptomycin -treated patients over 7 days. CONCLUSIONS:These data underscore the importance of ?-lactams for SaB, including consideration that the adjunctive role of ?-lactams for MRSA in select patients helps elicit favorable host cytokine responses.
| S-EPMC7286365 | biostudies-literature
Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a major hospital- and community-acquired pathogen, but the mechanisms underlying host-defense to MRSA remain poorly understood. Here, we investigated the role of IL-21 in this process. When administered intra-tracheally into wild-type mice, IL-21 induced granzymes and augmented clearance of pulmonary MRSA but not when neutrophils were depleted or a granzyme B inhibitor was added. Correspondingly, IL-21 induced MRSA killing by human peripheral blood neutrophils. Unexpectedly, however, basal MRSA clearance was also enhanced when IL-21 signaling was blocked, both in Il21r KO mice and in wild-type mice injected with IL-21R-Fc fusion-protein. This correlated with increased type I interferon and an IFN-related gene signature, and indeed anti-IFNAR1 treatment diminished MRSA clearance in these animals. Moreover, we found that IFNβ induced granzyme B and promoted MRSA clearance in a granzyme B-dependent fashion. These results reveal an interplay between IL-21 and type I IFN in the innate immune response to MRSA.
| S-EPMC6504231 | biostudies-literature
Project description:Oncogenic driver mutations in several tumor types promote constitutive PD-L1 expression, a crucial ligand in PD-1-mediated tumor immune escape. Our studies in melanoma suggest a different mechanism-one of "adaptive immune resistance" in which PD-L1 expression is primarily driven by cytokine induction and is independent of BRAF mutational status.
| S-EPMC4589064 | biostudies-literature
Project description:BackgroundTreatment multiple tumors by immune therapy can be achieved by mobilizing both innate and adaptive immunity. The programmed death ligand 1 (PD-L1; or CD274, B7-H1) is a critical "don't find me" signal to the adaptive immune system. Equally CD47 is a critical "don't eat me" signal to the innate immune system and a regulator of the adaptive immune response.MethodBoth of CD47 and PD-L1 are overexpressed on the surface of cancer cells to enable to escape immune-surveillance. We designed EpCAM (epithelial cell adhesion molecule)-targeted cationic liposome (LPP-P4-Ep) containing si-CD47 and si-PD-L1 could target high-EpCAM cancer cells and knockdown both CD47 and PD-L1 proteins.FindingsEfficient silencing of CD47 and PD-L1 versus single gene silencing in vivo by systemic administration of LPP-P4-Ep could significantly inhibited the growth of solid tumors in subcutaneous and reduced lung metastasis in lung metastasis model. Target delivery of the complexes LPP-P4-Ep increased anti-tumor T cell and NK cell response, and release various cytokines including IFN-γ and IL-6 in vivo and in vitro.InterpretationThis multi-nanoparticles showed significantly high-EpCAM tumor targeting and lower toxicity, and enhanced immune therapeutic efficacy. Our data indicated that dual-blockade tumor cell-specific innate and adaptive checkpoints represents an improved strategy for tumor immunotherapy. FUND: This research supported by the Ministry of Science and Technology of the People's Republic of China (grant number 2015CB931804); the National Natural Science Foundation of China (NSFC, grant numbers 81703555, U1505225 and 81773063), and the China Postdoctoral Science Foundation (grant number 2017 M620268).
| S-EPMC6491392 | biostudies-literature
Project description:Staphylococcus aureus persistently colonises the anterior nares of a significant proportion of the healthy population, however the local immune response elicited during S. aureus nasal colonisation remains ill-defined. Local activation of IL-17/IL-22 producing T cells are critical for controlling bacterial clearance from the nasal cavity. However, recurrent and long-term colonisation is commonplace indicating efficient clearance does not invariably occur. Here we identify a central role for the regulatory cytokine IL-10 in facilitating bacterial persistence during S. aureus nasal colonisation in a murine model. IL-10 is produced rapidly within the nasal cavity following S. aureus colonisation, primarily by myeloid cells. Colonised IL-10-/- mice demonstrate enhanced IL-17+ and IL-22+ T cell responses and more rapidly clear bacteria from the nasal tissues as compared with wild-type mice. S. aureus also induces the regulatory cytokine IL-27 within the nasal tissue, which acts upstream of IL-10 promoting its production. IL-27 blockade reduces IL-10 production within the nasal cavity and improves bacterial clearance. TLR2 signalling was confirmed to be central to controlling the IL-10 response. Our findings conclude that during nasal colonisation S. aureus creates an immunosuppressive microenvironment through the local induction of IL-27 and IL-10, to dampen protective T cell responses and facilitate its persistence.
| S-EPMC9282462 | biostudies-literature
Project description:The host immune system generally serves as a barrier against tumor formation. Programmed death-ligand 1 (PD-L1) is a critical "don't find me" signal to the adaptive immune system, whereas CD47 transmits an anti-phagocytic signal, known as the "don't eat me" signal, to the innate immune system. These and similar immune checkpoints are often overexpressed on human tumors. Thus, dual targeting both innate and adaptive immune checkpoints would likely maximize anti-tumor therapeutic effect and elicit more durable responses. Herein, based on the variable region of atezolizumab and consensus variant 1 (CV1) monomer, we constructed a dual-targeting fusion protein targeting both CD47 and PD-L1 using "Knobs-into-holes" technology, denoted as IAB. It was effective in inducing phagocytosis of tumor cells, stimulating T-cell activation and mediating antibody-dependent cell-mediated cytotoxicity in vitro. No obvious sign of hematological toxicity was observed in mice administered IAB at a dose of 100 mg/kg, and IAB exhibited potent antitumor activity in an immune-competent mouse model of MC38. Additionally, the anti-tumor effect of IAB was impaired by anti-CD8 antibody or clodronate liposomes, which implied that both CD8+ T cells and macrophages were required for the anti-tumor efficacy of IAB and IAB plays an essential role in the engagement of innate and adaptive immune responses. Collectively, these results demonstrate the capacity of an elicited endogenous immune response against tumors and elucidate essential characteristics of synergistic innate and adaptive immune response, and indicate dual blockade of CD47 and PD-L1 by IAB may be a synergistic therapy that activates both innate and adaptive immune response against tumors.
| S-EPMC5825205 | biostudies-literature
Project description:Background & aimsThe liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo.MethodsTo induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10.ResultsWe found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions.ConclusionsTreg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases.Impact and implicationsLiver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.
| S-EPMC10964083 | biostudies-literature
Project description:There is no effective therapy for implant-associated Staphylococcus aureus osteomyelitis, a devastating complication after orthopedic surgery. An immune-suppressive profile with up-regulated programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) was identified based on our transcriptional data (GEO: GSE166522) from a mouse model of S. aureus osteomyelitis. PD-1/PD-L1 expression was up-regulated mainly in F4/80+ macrophages surrounding the abscess in S. aureus-infected bone. Mechanistically, PD-1/PD-L1 activated mitophagy to suppress production of mitochondrial reactive oxygen species (ROS), suppressing the bactericidal function of macrophages. Using neutralizing antibodies for PD-L1 or PD-1, or knockout of PD-L1 adjuvant to gentamicin markedly reduced mitophagy in bone marrow F4/80+ cells, enhanced bacterial clearance in bone tissue and implants, and reduced bone destruction in mice. PD-1/PD-L1 expression was also increased in the bone marrow from individuals with S. aureus osteomyelitis. These findings uncover a so far unknown function of PD-1/PD-L1-mediated mitophagy in suppressing the bactericidal function of bone marrow macrophages.
| S-EPMC9840119 | biostudies-literature
Project description:Staphylococcus aureus is a frequent commensal but also a dangerous pathogen, causing many forms of infection ranging from mild to life-threatening conditions. Among its virulence factors are lipoproteins, which are anchored in the bacterial cell membrane. Lipoproteins perform various functions in colonization, immune evasion, and immunomodulation. These proteins are potent activators of innate immune receptors termed Toll-like receptors 2 and 6. This study addressed the specific B-cell and T-cell responses directed to lipoproteins in human S. aureus carriers and non-carriers. 2D immune proteomics and ELISA approaches revealed that titers of antibodies (IgG) binding to S. aureus lipoproteins were very low. Proliferation assays and cytokine profiling data showed only subtle responses of T cells; some lipoproteins did not elicit proliferation. Hence, the robust activation of the innate immune system by S. aureus lipoproteins does not translate into a strong adaptive immune response. Reasons for this may include inaccessibility of lipoproteins for B cells as well as ineffective processing and presentation of the antigens to T cells.
| S-EPMC5096053 | biostudies-literature
Project description:IntroductionTumor immunotherapy targeting PD-L1 has emerged as one of the powerful tools for tumor therapy. Numerous studies indicate that tumor-targeted drugs critically have an influence on the interaction between the immune system and tumors by changing the expression of PD-L1, which is beneficial for immunotherapy. Our study provided novel evidence for improving the drug regimen in tumor targeted therapy and immunotherapy.MethodsThe expression of PD-L1 on SKBR3, MDA-MB-231, MCF7, 4T1, MC38 and B16 cells was evaluated by flow cytometry after treatment with six preclinical targeted drugs (ARN-509, AZD3514, Galeterone, Neratinib, MLN8237 and LGK974). AURKA was knockdowned by using the specific siRNA or CRISPR-Cas9 technology. In the 4T1-breast tumor and colorectal cancer xenograft tumor models, we determined the number of infiltrated CD3+ and CD8+ T cells in tumor tissues by IHC.ResultsWe found that AURKA inhibitor MLN8237 promoted the expression of PD-L1 in a time- and concentration-dependent manner while exerted its antitumor effect. Knockdown of AURKA could induce the upregulation of PD-L1 on SKBR3 cells. MLN8237-induced PD-L1 upregulation was mainly associated with the phosphorylation of STAT3. In the 4T1-breast tumor xenograft model, the infiltrated CD3+ and CD8+ T cells decreased after treatment with MLN8237. When treated with MLN8237 in combination with anti-PD-L1 antibody, the volumes of tumor were significantly reduced and accompanied by increasing the infiltration of CD3+ and CD8+ T cells in colorectal cancer xenograft tumor model.DiscussionOur data demonstrated that MLN8237 improved the effect of immunology-related therapy on tumor cells by interacting with anti-PD-L1 antibody, which contributed to producing creative sparks for exploring the possible solutions to overcoming drug resistance to tumor targeted therapy.
| S-EPMC10536236 | biostudies-literature