Biology subjects

Rajendran, B. K.

Publications and source records attributed to Rajendran, B. K..

4 recordsLinked to original sources

bioRxiv2023

Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease

Angiopoietin-like 4 (ANGPTL4) is the key protein involved in lipoprotein metabolism and has been shown to have diverse effects on tissue protection. In clinical settings, there is a reported association between higher levels of plasma Angptl4 and features of diabetic kidney disease, however, the association between kidney Angptl4 with features of diabetic kidney disease has not been well investigated. We show that both podocyte-and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Results from mRNA-array analysis in control (non-fibrotic) and diabetic (fibrotic) kidneys suggest time-dependent emergence of Angplt4 expression. Diabetes accelerates the fibrogenic phenotype in control mice but not in ANGPTL4 mutant mice. The protective effect observed in ANGPTL4 mutant mice is correlated with a reduction in the levels of pro-inflammatory cytokines, epithelial-to-mesenchymal transition, endothelial-to-mesenchymal transition and augmented fatty acid oxidation. Mechanistically, we demonstrate that podocyte-or tubule-secreted Angptl4 interacts with Integrin-{beta}1 and influences the association between dipeptidyl-4 with Integrin-{beta}1 and promotes heterodimerization of transforming growth factor-{beta} receptor 1 (TGF{beta}R1) and TGF{beta}R2 in cultured cells. This in turn results in Smad3 phosphorylation and subsequent downregulation of the expression of genes involved in fatty acid oxidation; these cumulative effects led to the activation of fibrogenic phenotypes. We demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the kidneys and protects diabetic kidneys from proteinuria and fibrosis. Importantly, use of this kidney-specific targeted strategy is beneficial and does not cause any harmful effect suggesting it can be used as a novel drug molecule for treatment of diabetic kidney disease. Taken together, these data demonstrate that podocyte-and tubule-derived Angptl4 is fibrogenic in diabetic kidneys.

cell biology↗

bioRxiv2023

Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

WNT5A and WNT5B are two close homologs, both of which are implicated in the pathogenesis of inflammatory bowel diseases. However, the roles these two proteins play in the disease remain largely uncharacterized. Here, we report that double knockout of Wnt5a and Wnt5b (Wnt5 DKO) protects mice from Dextran Sodium Sulfate (DSS)-induced colitis in mice, accompanied with greater splenomegaly, stronger expansion of peripheral myeloid cells, and less colonic CD8+ T cell granzyme B expression than those of the control mice. Depletion of neutrophils or splenectomy abrogates the phenotypic differences between Wnt5 DKO and control mice largely by exacerbating colitis phenotypes and increasing colonic CD8+ T cell GZMB expression in the Wnt5 DKO mice. In addition, neutrophils from the Wnt5 DKO colitic mice exert stronger suppression of CD8+ T cells than those from the control mice in culture. Single-cell RNA sequencing and proteomic analyses indicate that neutrophils from DSS-treated Wnt5 DKO mice are of hyper-immunosuppressive and hypo-inflammatory characteristics and are distinct from those of DSS-treated control mice as well as myeloid-derived suppressor cells in tumor-bearing mice. Thus, our study reveals that the lack of WNT5 reprograms neutrophils in spleens to limit colonic injury during DSS-induced colitis.

immunology↗

bioRxiv2023

Lack of Fzd6 in Ciliated Cells Suppresses Ferroptotic Pulmonary Alveolar Cell Death Induced by LPS and Coronavirus

Pulmonary inflammation compromises lung barrier function and underlies many lung diseases including acute lung injury and acute respiratory distress syndrome (ARDS). However, mechanisms by which lung cells respond to the damage caused by the inflammatory insults are not completely understood. Here we show that Fzd6-deficiency in Foxj1+ ciliated cells reduces pulmonary permeability, lipid peroxidation, and alveolar cell death accompanied with an increase in alveolar number in lungs insulted by LPS or a mouse coronavirus. Single-cell RNA sequencing of lung cells indicates that the lack of Fzd6, which is expressed in Foxj1+ cells, increases expression of the aldo-keto reductase Akr1b8 in Foxj1+ cells. Intratracheal administration of the Akr1b8 protein phenocopies Fzd6-deficient lung phenotypes. In addition, ferroptosis inhibitors also phenocopy Fzd6-deficient lung phenotypes and exert no further effects in Fzd6-deficient lungs. These results reveal an important mechanism for protection of alveolar cells from ferroptotic death during pulmonary inflammation by Foxj1+ ciliated cells via paracrine action of Akr1b8.

pathology↗

bioRxiv2022

The Cul5 E3 Ligase Complex Is a Key Negative Feedback Regulator of TCR/IL2 Signaling and Anti-Tumor Activity in CD8+ T Cells

CD8+ T cells play an important role in tumor immune surveillance and control. Better understanding of the regulation of their anti-tumor actions and improving their cytotoxic function and persistence will help advancing cancer immunotherapies. Here, we report the development of a step-wise CRISPR knockout (KO) screening strategy under the selection of TGF-{beta}, a clinically relevant immunosuppressive pressure. The screen identifies Cul5 as a negative-feedback regulator of the core signaling pathways, differentiation, and persistence of CD8+ T cell. Cul5 KO in mouse CD8+ T cells significantly improves their tumor control ability in vitro and in vivo with significant proteomic alterations that generally enhance TCR and cytokine signaling, effector function, stemness, and survival of CD8+ T cell. Mechanistically, Cul5, whose protein content and active, neddylated form increase upon TCR-stimulation, interacts with SOCS-box-containing Pcmtd2 and negatively regulates TCR and IL2/STAT5 signaling by decreasing TCR and IL2 signaling molecules. Moreover, Cul5 KO in human CD8+ T cells phenocopies that in mouse CD8+ T cells. Furthermore, KO of CTLA4 that is markedly upregulated by Cul5 KO in mouse and human CD8+ cells further enhances anti-tumor effect of Cul5 KO, and a neddylation inhibitor enhances CD8 effector activities largely dependently of Cul5. These results together not only reveal a previously unknown negative-feedback regulatory mechanism for CD8+ T cells, but also have strong translational implications in cancer immunotherapy.

immunology↗