Biology subjects

Kissler, S.

Publications and source records attributed to Kissler, S..

5 recordsLinked to original sources

bioRxiv2024

Renalase inhibition regulates β cell metabolism to defend against acute and chronic stress

Renalase (Rnls), annotated as an oxidase enzyme, is a GWAS gene associated with Type 1 Diabetes (T1D) risk. We previously discovered that Rnls inhibition delays diabetes onset in mouse models of T1D in vivo, and protects pancreatic {beta} cells against autoimmune killing, ER and oxidative stress in vitro. The molecular biochemistry and functions of Rnls are entirely uncharted. Here we find that Rnls inhibition defends against loss of {beta} cell mass and islet dysfunction in chronically stressed Akita mice in vivo. We used RNA sequencing, untargeted and targeted metabolomics and metabolic function experiments in mouse and human {beta} cells and discovered a robust and conserved metabolic shift towards glycolysis, amino acid abundance and GSH synthesis to counter protein misfolding stress, in vitro. Our work illustrates a function for Rnls in mammalian cells, and suggests an axis by which manipulating intrinsic properties of {beta} cells can rewire metabolism to protect against diabetogenic stress.

physiology↗

bioRxiv2024

Beta Cells Deficient for Renalase Counteract Autoimmunity by Shaping Natural Killer Cell Activity

Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells. Genetic engineering is a promising approach to enhance immune resistance of beta cells as we previously showed by inactivating of the Renalase (Rnls) gene. Here we demonstrate that Rnls loss-of-function in beta cells shape autoimmunity by mediating a regulatory Natural Killer (NK) cell phenotype important for the induction of tolerogenic antigen presenting cells. Rnls-deficient beta cells mediate cell-cell-contact-independent induction of hallmark anti-inflammatory cytokine Tgf{beta}1 in NK cells. In addition, surface expression of key regulatory NK immune checkpoints CD47 and Ceacam1 are markedly elevated on beta cells deficient for Rnls. Enhanced glucose metabolism in Rnls mutant beta cells is responsible for upregulation of CD47 surface expression. These findings are crucial to a better understand how genetically engineered beta cells shape autoimmunity giving valuable insights for future therapeutic advancements to treat and cure T1D. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/582816v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@175f849org.highwire.dtl.DTLVardef@1ff9c0aorg.highwire.dtl.DTLVardef@5d7f9borg.highwire.dtl.DTLVardef@64b2f2_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Gata3 is detrimental to regulatory T cell function in autoimmune diabetes

Regulatory T cells (Tregs) protect against autoimmunity. In type 1 diabetes (T1D), Tregs slow the progression of beta cell autoimmunity within pancreatic islets. Increasing the potency or frequency of Tregs can prevent diabetes, as evidenced by studies in the nonobese diabetic (NOD) mouse model for T1D. We report herein that a significant proportion of islets Tregs in NOD mice express Gata3. The expression of Gata3 was correlated with the presence of IL-33, a cytokine known to induce and expand Gata3+ Tregs. Despite significantly increasing the frequency of Tregs in the pancreas, exogenous IL-33 was not protective. Based on these data, we hypothesized that Gata3 is deleterious to Treg function in autoimmune diabetes. To test this notion, we generated NOD mice with a Treg-specific deletion of Gata3. We found that deleting Gata3 in Tregs strongly protected against diabetes. Disease protection was associated with a shift of islet Tregs toward a suppressive CXCR3+Foxp3+ population. Our results suggest that islet Gata3+ Tregs are maladaptive and that this Treg subpopulation compromises the regulation of islet autoimmunity, contributing to diabetes onset.

immunology↗

bioRxiv2020

Glycocalyx-mediated Cell Adhesion and Migration

Cell migration is a force-dependent adaptive process mediated by integrin-dependent adhesion as well as other yet poorly defined interactions to the extracellular matrix. Using enzymatic multi-targeted digestion of sugar moieties on the surface of mesenchymal cells and leukocytes after interference with integrin function, we demonstrate that the surface glycocalyx represents an independent adhesion system. The glycocalyx mediates cell attachment to ECM ligand in the 100-500 pN force range and amoeboid migration in 3D environments in vitro and in vivo. Glycan-based adhesions consist of actin-rich membrane deformations and appositions associated with bleb-like and other protrusions forming complex-shaped sub-micron contact sites to ECM fibrils. These data implicate the glycocalyx in mediating generic stickiness to support nanoscale interactions (nanogrips) between the cell surface and ECM, mechano-coupling, and migration.

cell biology↗

bioRxiv2017

Peripherally-induced regulatory T cells contribute to the control of autoimmune diabetes

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells and is partly caused by deficiencies in the Foxp3+ regulatory T cell (Treg) compartment. Conversely, therapies that increase Treg function can prevent autoimmune diabetes in animal models. The majority of Tregs develop in the thymus (tTregs), but a proportion of Foxp3+ Tregs is generated in the periphery (pTregs) from Foxp3-CD4+ T cell precursors. Whether pTregs play a distinct role in T1D has not yet been explored. We report here that pTregs are a key modifier of disease in the nonobesed diabetic (NOD) mouse model for T1D. We generated NOD mice deficient for the Foxp3 enhancer CNS1 involved in pTreg induction. We show that CNS1 knockout decreased the frequency of pTregs and increased the risk of diabetes. Our results show that pTregs fulfill an important non-redundant function in the prevention of beta cell autoimmunity that causes T1D.

immunology↗