Biology subjects

Biradar, S.

Publications and source records attributed to Biradar, S..

4 recordsLinked to original sources

bioRxiv2025

NRF2-Dependent Anti-Inflammatory Activity of Indole via Cell Surface Receptor Signaling in Murine Macrophages

In this study, we report indoles anti-inflammatory effects to be AhR-independent in RAW 264.7 macrophages. To explore the possibility of indoles surface-receptor mediated signaling, we developed an indole-bovine serum albumin conjugate (I3B), which primarily engage cell surface receptors and has limited intracellular engagement. Treatment with 10 M of I3B led to a comparable reduction of TNF- production in LPS-stimulated RAW 264.7 macrophages to that observed with 500 M of free indole. Transcriptome profiling of I3B-treated LPS-stimulated RAW 264.7 macrophages revealed, I3B blunts pro-inflammatory response and induces gene signatures consistent with NRF2 activation. LPS-stimulated NRF2-/- Bone Marrow-derived Macrophages (BMM) treated with I3B, showed higher levels of pro-inflammatory cytokine production relative to non-treated BMM. To define the upstream pathways responsible for this NRF2-depedent response, we examined GPCR-mediated signaling and found that I3B engages a Gq-coupled receptor to induce PKC{delta} phosphorylation, and subsequent NRF2 phosphorylation. Our results suggest I3B signals through a surface-receptor in a NRF2-dependent manner to reduce inflammation in murine macrophages. TeaserA cell-impermeant indole conjugate inhibits inflammatory signaling in macrophages through an NRF2-dependent mechanism.

cell biology↗

bioRxiv2021

Adoptive transfer of allogeneic gamma delta T cells promotes HIV replication in a humanized mouse model

Gamma-delta ({gamma}{delta}) T cells recognize antigens in an MHC-independent manner, with demonstrable cytotoxicity against cancer and virally infected cells. Human immunodeficiency virus (HIV) infection severely depletes the V{gamma}9V{delta}2 (V{delta}2) subset of these T cells in most infected individuals, with the exception of elite controllers. The capacity of V{delta}2 cells to kill HIV-infected targets has been demonstrated in vitro, but this has not been verified in vivo. Here, we examined the immunotherapeutic potential of V{delta}2 cells in controlling HIV replication in vivo and provide the first characterization of reconstituted {gamma}{delta} T cell subsets in the peripheral blood and lymphoid tissue in a humanized mouse model. We demonstrate the depletion of V{delta}2 cells and increase in V{delta}1 cells in the blood following HIV infection, similar to that observed in HIV-infected humans. The functionality of human V{delta}2 cells isolated from humanized mice was confirmed via ex vivo expansion in response to zoledronate and IL-2 treatment. The adoptive transfer of activated V{delta}2 cells failed to control HIV infection in vivo but instead exacerbated viremia by serving as early targets for HIV infection. Our findings suggest that V{delta}2 cells play a critical and unappreciated role as early HIV targets of infection to promote viral dissemination.

immunology↗

bioRxiv2021

Nef dimerization defect abrogates HIV viremia and associated immune dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) humanized mouse model

Loss of function mutations in the human immunodeficiency virus (HIV) negative factor (Nef) gene are associated with reduced viremia, robust T cell immune responses, and delayed acquired immunodeficiency syndrome (AIDS) progression in humans. In vitro studies have shown that mutations in the Nef dimerization interface significantly attenuate viral replication and impair host defense. However, in vivo, mechanistic studies on the role of Nef dimerization in HIV infection are lacking. Humanized rodents with human immune cells are robust platforms for investigating the interactions between HIV and the human immune system. The bone marrow-liver-thymus-spleen (BLTS) humanized mouse model carries human immune cells and lymphoid tissues that facilitate anti-viral immune responses. Here, we employed the BLTS-humanized mouse model to demonstrate that preventing Nef dimerization abrogates HIV viremia and the associated immune dysregulation. This suggests that Nef dimerization may be a therapeutic target for future HIV cure strategies.

immunology↗

bioRxiv2020

Development of humanized mouse and rat models with full-thickness human skin and autologous immune cells

The human skin is a major barrier for host defense against many human pathogens, with several pathogens directly targeting the skin for replication and disease. The skin is also the primary route of infection for a myriad of vector-borne diseases; thus cutaneous immune cells play a major role in modulating transmission for such infectious diseases. Several human pathogens that target the skin as a major route of infection are unable to infect traditional rodent models or recapitulate the pathogenesis in humans. It is well established that differences exist in human skin and immune cell biology compared to rodent models. Therefore, rodent (mouse and rat) models that incorporate human skin and immune cells would addressed the above discussed technical gap, and enable in vivo mechanistic studies of human host-skin pathogen interactions, and support the development of novel therapeutics. Here, we introduce the novel human Skin and Immune System (hSIS)-humanized NOD-scid IL2Rgnull (NSG) mouse and Sprague-Dawley-Rag2tm2hera Il2rgtm1hera (SRG) rat models, co-engrafted with full-thickness human fetal skin, autologous fetal lymphoid tissues, and fetal liver-derived hematopoietic stem cells. hSIS-humanized rodents support the development of adult-like, full-thickness human skin and human lymphoid tissues, and support human immune cell development. Furthermore, the engrafted human skin supports Methicillin-resistant Staphylococcus aureus infection, demonstrating the utility of these humanized rodent models in studying human disease.

immunology↗