Biology subjects

Shayakhmetov, D. M.

Publications and source records attributed to Shayakhmetov, D. M..

4 recordsLinked to original sources

bioRxiv2022

A paracrine circuit of IL-1b/IL-1R1 between myeloid and tumor cells drives glioblastoma progression

Monocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate and promote glioblastoma growth. Here we discover that glioma cells induce the expression of potent pro-inflammatory cytokine IL-1{beta} in MDM, which engages IL-1R1 in glioma cells, activates NF-{kappa}B pathway, and subsequently leads to the induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1{beta}/IL-1R1 between the tumors and MDM creates an interdependence driving glioblastoma progression. Locally antagonizing IL-1{beta}/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, reduced exhausted CD8+ T cells, and thereby extends the survival of tumor-bearing mice. In contrast to IL-1{beta}, IL-1a exhibits anti-tumor effects. Genetic deletion of Il1a is associated with decreased recruitment of lymphoid cells and loss of interferon (IFN) signaling in various immune populations and subsets of malignant cells. IL-1{beta} antagonism of IL-1{beta} should be considered as an effective anti-glioblastoma therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/486888v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1c99e57org.highwire.dtl.DTLVardef@1ba9d24org.highwire.dtl.DTLVardef@a2c418org.highwire.dtl.DTLVardef@1f8091c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

TRAF6-IRF5 kinetics, TRIF, and biophysical factors drive synergistic innate responses to particle-mediated MPLA-CpG co-presentation

Innate immune responses to pathogens are driven by co-presentation of multiple pathogen-associated molecular patterns (PAMPs). PAMPs and PAMP-analogs are also used as immune-adjuvants to enhance vaccine efficacy by activating various Pattern Recognition Receptors (PRRs), like Toll-like receptors (TLRs). Various combinations of PAMP adjuvants can trigger synergistic immune responses, but the underlying molecular mechanisms driving that synergy are poorly understood. Here, we used synthetic particulate carriers co-loaded with MPLA (TLR4-adjuvant) and CpG (TLR9-adjuvant) as pathogen-like particles (PLPs) to dissect the signaling pathways responsible for the integrated, dual-adjuvant immune response. PLP-based co-presentation of MPLA and CpG to mouse bone marrow derived antigen-presenting cells (BM-APCs) elicited synergistic Type-I Interferon (IFN-{beta}) and IL-12p70 responses, which were strongly influenced by the biophysical properties of PLPs. Mechanistically, we found that the adapter protein MyD88 and the Interferon-Regulatory-Factor-5 (IRF-5), but not the canonical factors IRF-3 or IRF-7, were necessary for production of both IFN-{beta} and IL12p70. TRIF signaling was required to elicit the synergistic response; the absence of TRIF abolished synergy. Importantly, both the kinetics and magnitude of downstream TRAF6 and IRF5 signaling (TRIF-TRAF-IRF5 pathway kinetics) drove the observed synergy. These results identify not only the key signaling mechanism that cooperates to generate a combinatorial response to MPLA-CpG dual engagement in BM-APCs, but they also underscore the critical role that signaling kinetics and biophysical presentation plays in integrated responses to combination adjuvants.

immunology↗

bioRxiv2020

Nano-Emulsion Adjuvant Enhances Cross-presentation by Lipid Body Formation Independent of Glycolysis

Here, we report that a carbomer-based adjuvant, Adjuplex(R) (ADJ), stimulated robust CD8 T-cell responses to subunit antigens by modulating multiple steps in the cytosolic pathway of cross-presentation, and afforded effective immunity against virus and intracellular bacteria. Cross-presentation induced by TLR agonists requires a critical switch to anabolic metabolism, but ADJ enhanced cross presentation without this metabolic switch in DCs and NLRP3-driven caspase 1 activity. Instead, ADJ induced in DCs, an unique metabolic state, typified by dampened oxidative phosphorylation and basal levels of glycolysis. In the absence of increased glycolytic flux, induction of ROS and lipid bodies (LBs) and alterations in LB composition mediated by ADJ were critical for DC cross-presentation. These findings challenge the prevailing metabolic paradigm by suggesting that DCs can perform effective DC cross-presentation, independent of glycolysis to induce robust T cell-dependent protective immunity to intracellular pathogens. These findings have implications in the rational development of novel adjuvants.

immunology↗

bioRxiv2019

Modification of primary amines to higher order amines reduces in vivo hematological and immunotoxicity of cationic nanocarriers through TLR4 and complement pathways

For decades, cationic polymer nanoparticles have been investigated for nucleic acid delivery. Despite promising in vitro transfection results, most formulations have failed to translate into the clinic due to significant in vivo toxicity - especially when delivered intravenously. To address this significant problem, we investigated the detailed mechanisms that govern the complex in vivo systemic toxicity response to common polymeric nanoparticles. We determined that the toxicity response is material dependent. For branched polyethylenimine (bPEI) nanoparticles - toxicity is a function of multiple pathophysiological responses - triggering of innate immune sensors, induction of hepatic toxicity, and significant alteration of hematological properties. In contrast, for chitosan-based nanoparticles - systemic toxicity is primarily driven through innate immune activation. We further identified that modification of primary amines to secondary and tertiary amines using the small molecule imidazole-acetic-acid (IAA) ameliorates in vivo toxicity from both nanocarriers by different, material-specific mechanisms related to Toll-like receptor 4 activation (for bPEI) and complement activation driven neutrophil infiltration (for chitosan), respectively. Our results provide a detailed roadmap for evaluating in vivo toxicity of nanocarriers and identifies potential opportunities to reduce toxicity for eventual clinical translation.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC=\"FIGDIR/small/647305v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (27K):\norg.highwire.dtl.DTLVardef@63c7a7org.highwire.dtl.DTLVardef@c8ac52org.highwire.dtl.DTLVardef@a9589dorg.highwire.dtl.DTLVardef@1f8ec62_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗