Biology subjects

LaFavers, K.

Publications and source records attributed to LaFavers, K..

4 recordsLinked to original sources

bioRxiv2026

Uromodulin promotes immune zonation and inhibits alternative inflammasome-mediated activation of immune-to-collecting duct inflammatory signaling in early acute kidney injury

Uromodulin, a protein made uniquely by the kidney, is protective against acute kidney injury. An integrated transcriptomic and multiplexed spatial protein imaging was used to uncover early cellular and molecular pathophysiological mechanisms following murine kidney ischemia and reperfusion injury (IRI) and better define the role of Uromodulin at the early stage of injury. Six hours following IRI, there was a pan-nephronal transcriptomic response with activation of common pathways but also unique gene expression signatures for each nephron segment. Cell-cell communications and epithelial-immune spatial interactions most prominently involved thick ascending limbs and distal nephron segments with distinct immune zonation in the inner stripe of the outer medulla. Uromodulin deficiency swayed the tubular transcriptomic signatures towards more severe injury and inflammation with altered macrophage communication. Uromodulin deficiency also caused partial loss of immune zonation and a shift towards broader epithelial-immune interactions in the outer stripe and cortex. Uromodulin inhibited activation of the Nlrc4-dependent alternative inflammasome pathway in macrophages, where the production of IL-1{beta} predominantly targets other immune and collecting duct (CD) cells. Indeed, Uromodulin deficiency induced the expression of CD8 in CD cells which acquire a proinflammatory phenotype linked to spatial niches containing immune cells. The presence of CD8+ CD cells was validated in human kidney biopsies. In conclusion, our findings support a role for Uromodulin in spatially confining the immune system around TAL cells in the inner stripe away from the vulnerable outer stripe in early injury. Uromodulin also inhibits the inflammasome-mediated macrophage-epithelial crosstalk that could induce collecting duct cells towards more inflammatory signaling.

physiology↗

bioRxiv2022

A spatially anchored transcriptomic atlas of the human kidney papilla identifies significant immune injury and matrix remodeling in patients with stone disease

Kidney stone disease causes significant morbidity and increases health care utilization. The pathogenesis of stone disease is not completely understood, due in part to the poor characterization of the cellular and molecular makeup of the kidney papilla and its alteration with disease. We deciphered the cellular and molecular niche of the human renal papilla in patients with calcium oxalate (CaOx) stone disease compared to healthy subjects using single nuclear RNA sequencing, spatial transcriptomics and high-resolution large-scale multiplexed 3D and Co-Detection by indexing (CODEX) imaging. In addition to identifying cell types important in papillary physiology, we defined subtypes of immune, stromal and principal cells enriched in the papilla, and characterized an undifferentiated epithelial cell cluster that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncovered a global injury signature involving multiple cell types within the papilla, characterized by immune activation, oxidative stress and extracellular matrix remodeling. The microenvironment of mineral deposition had features of an immune synapse with antigen presenting inflammatory macrophages interacting with T cells, and an immune repertoire ranging from inflammation to fibrosis. The expression of MMP7 and MMP9 was associated with stone disease and mineral deposition, respectively. MMP7 and MMP9 were significantly increased in the urine of patients with CaOx stone disease compared to non-stone formers, and their levels correlated with disease activity in stone formers. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla, and identify potential urinary biomarkers.

genomics↗

bioRxiv2022

The dually localized EF-hand domain-containing protein TgEFP1 regulates the lytic cycle of Toxoplasma gondii

The propagation of the obligate intracellular parasite Toxoplasma gondii is tightly regulated by calcium signaling. However, the mechanisms by which calcium homeostasis and fluxes are regulated in this human pathogen are not fully understood. To identify Toxoplasmas calcium homeostasis network, we have characterized a novel EF-hand domain-containing protein, which we have named TgEFP1. We have determined that TgEFP1 localizes to a previously described compartment known as the plant-like vacuole or the endo-lysosomal compartment (PLV/ELC), which harbors several proteins related to ionic regulation. Interestingly, partial permeabilization techniques showed that TgEFP1 is also secreted into the parasitophorous vacuole (PV), within which the parasite divides. Ultrastructure expansion microscopy confirmed the unusual dual localization of TgEFP1 at the PLV/ELC and the PV. Furthermore, we determined that the localization of TgEFP1 to the PV, but not to the PLV/ELC, is affected by disruption of Golgi-dependent transport with Brefeldin A. Knockout of TgEFP1 results in faster propagation in tissue culture, hypersensitivity to calcium ionophore-induced egress, and premature natural egress. Thus, our work has revealed an interplay between the PV and the PLV/ELC and a role for TgEFP1 in the regulation of calcium-dependent events.

microbiology↗

bioRxiv2021

The kidney protects against sepsis by enhancing the systemic release of Uromodulin to stimulate macrophage function

Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. While electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We previously demonstrated that systemic Tamm-Horsfall Protein (THP, uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we show that the kidney increases circulating THP by enhancing basolateral release of THP from medullary thick ascending limb cells. In sepsis patients, changes in circulating THP are positively associated with critical illness. THP is also found de novo in injured lungs. Genetic ablation of THP in mice leads to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo leads macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis and chemotaxis and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improves survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function and systemic THP has therapeutic potential in sepsis. Significance StatementSepsis is a significant contributor to kidney injury as well as morbidity and mortality worldwide. Specific therapies to improve outcomes in sepsis with kidney injury have largely been limited to symptom management and infectious agent control, in part because it is unclear how kidney injury increases sepsis mortality. This paper describes the identification of Tamm-Horsfall protein, previously known to protect in ischemic models of AKI, as protective in preclinical models of sepsis. It demonstrates how the loss of THP leads to decreased mononuclear phagocyte function and diversity, increased pathogen burden and decreased survival. THP also increases in sepsis without severe kidney injury and concentrates in injured organs. Further study of THP in sepsis could lead to novel sepsis therapeutics.

immunology↗