Biology subjects

Hartner, S.

Publications and source records attributed to Hartner, S..

4 recordsLinked to original sources

bioRxiv2026

DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity

Over one million patients receive cancer immunotherapy annually, yet the mechanisms underlying life-threatening immune-mediated toxicities remain poorly understood. Checkpoint inhibitor pneumonitis (CIP) is the leading cause of immunotherapy-related mortality, with a case fatality rate approaching 10%, and no genetic risk factors have been described to date. We identified Dipeptidyl-peptidase 9 (DPP9) as the first genetic susceptibility gene for CIP in a clinico-genomics cohort of 4,397 patients treated with immune checkpoint inhibitors. Mechanistically, DPP9 suppresses CARD8 inflammasome activation and IL-18 secretion in human monocytes, a pathway which is engaged prior to CIP onset, with IL-18 selectively elevated in the plasma of patients who subsequently develop CIP. Myeloid-restricted ablation of Dpp8 and Dpp9 in mice recapitulated the pulmonary histopathological and immunological hallmarks of CIP, including granuloma formation, accumulation of IFN{gamma}-producing T cells and monocyte-derived macrophages. Each of these phenotypes were driven by excessive IL-18 secretion. Together, these findings establish DPP9 as a genetic determinant of CIP and nominate IL-18 blockade as a mechanistically rational therapeutic strategy.

immunology↗

bioRxiv2025

Acute Effects of Intra-Articular Liposomal IDO-1 following Anterior Cruciate Ligament Injury

Joint injuries, such as rupture of the anterior cruciate ligament (ACL), is associated with the development of post-traumatic osteoarthritis (PTOA). It is known that ACL rupture can lead to disruption of metabolic pathways, including the conversion of the essential amino acid tryptophan to kynurenine, which is associated with a sustained inflammatory response. An in vivo study was undertaken to determine the acute effects of intra-articular administration of liposomes loaded with the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-1 (IDO-1) following ACL rupture. Using an established rat model of non-surgical ACL injury, male and female Lewis rats underwent a single intra-articular injection of empty liposomes, or liposomes loaded with IDO-1 and were subsequently randomized to 1- or 2-week endpoints. IDO-1 treatment after ACL injury was associated with a significant reduction in synovial fluid concentration of tryptophan at both 1-and 2-week endpoints. In addition to a reduction in tryptophan, IDO-1 treatment led to significantly lower synovial fluid concentrations of IL-1b and TNF-a. Intra-articular administration of IDO-1-loaded liposomes also increased the ratio of regulatory T lymphocytes (Tregs) to IL-17-secreting helper T lymphocytes (Th17 cells). Similarly, IDO-1 treatment increased the number of CTLA4+ cells relative to IL-17A+ cells that infiltrated joint tissues at a 2-week endpoint. Contrast-enhanced micro-computed tomography (CE-uCT) was used to quantify treatment-based effects on articular cartilage thickness and surface roughness at at 2-week endpoint. In addition to sex-based differences, IDO-1-loaded liposome treatment was associated with increased cartilage thickness, with no significant effects on surface roughness. Histologic characterization is needed to determine whether this increased cartilage thickness represents a chondroprotective effect, or a degenerative effect of IDO-1-treatment.

physiology↗

bioRxiv2023

Progressive plasticity during colorectal cancer metastasis

Metastasis is the principal cause of cancer death, yet we lack an understanding of metastatic cell states, their relationship to primary tumor states, and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that while primary tumors largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Loss of intestinal cell states is accompanied by reprogramming into a highly conserved fetal progenitor state, followed by non-canonical differentiation into divergent squamous and neuroendocrine-like states, which is exacerbated by chemotherapy and associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cancer cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a stabilizer of intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming.

cancer biology↗

bioRxiv2021

Early Patellofemoral Cartilage and Bone Degeneration in a Rat Model of Noninvasive Anterior Cruciate Ligament Rupture

BackgroundAnterior cruciate ligament rupture (ACLR) is a well-known risk factor for the development of post-traumatic osteoarthritis (PTOA). While clinical and pre-clinical studies have characterized the onset and progression of PTOA in the tibiofemoral joint compartment, very little is known about degenerative changes in the patellofemoral compartment after ACL injury. Hypothesis/PurposeTo evaluate the extent to which ACL rupture induces acute patellofemoral joint degeneration by quantifying articular cartilage morphology and remodeling of subchondral and trabecular bone microarchitecture in the patellofemoral compartment. Study DesignDescriptive laboratory study. MethodsAdult female Lewis rats were randomized to undergo either a non-surgical ACL rupture or a Sham procedure (n = 6 per group). Ex vivo contrast-enhanced micro-computed tomography ({micro}CT) and histological evaluation of the patellofemoral compartment were performed at 2-weeks post-injury, representing a timepoint of documented early PTOA in the tibiofemoral compartment in this model. ResultsACL rupture causes osteophyte formation in the patella and mild degeneration in the superficial zone of articular cartilage (AC), including surface fibrillation, fissures, increased cellularity, and abnormal chondrocyte clustering at two weeks post-injury. Contrast-enhanced {micro}CT analysis demonstrates significant increases in AC thickness of patellar and trochlear cartilage. Loss of subchondral bone thickness, bone volume fraction, and tissue mineral density, as well as changes to trabecular microarchitecture in both the patella and trochlea, were indicative of catabolic bone remodeling. ConclusionThese results demonstrate that the patellofemoral joint develops mild but evident degenerative changes in the acute time period following ACL rupture, extending the utility of this rat model to the study of degenerative patellofemoral changes following joint trauma. Clinical RelevanceACL rupture causes mild degeneration and swelling of articular cartilage, coupled with catabolic bone remodeling in the patellofemoral compartment. Characterizing the pathophysiology of patellofemoral PTOA in its early stages may provide a better understanding of disease progression and provide opportunities for preventative therapeutic intervention.

physiology↗