Biology subjects

Heine, H.

Publications and source records attributed to Heine, H..

8 recordsLinked to original sources

bioRxiv2025

JNK integrates immune and stress signals to balance apoptosis and proliferation in airway progenitors

Chronic inflammation disrupts epithelial regeneration, yet how immune signaling reprograms progenitor fate remains unclear. Using the Drosophila airway as a model of epithelial remodeling, we identify the c-Jun N-terminal kinase (JNK) pathway as a central integrator of immune and stress cues that balances apoptosis and compensatory proliferation in airway progenitors. Persistent activation of the innate immune IMD pathway induces simultaneous cell death and proliferation through a non-canonical route that bypasses NF-{kappa}B/Relish and instead engages JNK. Downstream, distinct transcriptional modules orchestrate these divergent fates: Foxo and AP-1 drive apoptosis, whereas the ETS factor Ets21C mediates proliferation. Genetic inhibition of JNK or its effectors restores progenitor homeostasis, while constitutive activation recapitulates inflammation-induced tissue remodeling. These responses are cell-autonomous, revealing that airway progenitors actively interpret immune and stress signals to determine their fate. Collectively, our findings uncover a modular signaling architecture that links inflammation to regeneration and highlight conserved JNK-dependent transcriptional programs as potential therapeutic targets to prevent progenitor exhaustion in chronic airway disease.

cell biology↗

bioRxiv2025

Differential methanogenic archaea-induced TLR8-dependent signaling is governed by NF-κB p65- and STAT1/2-controlled gene classes

Prevalent in the human gut yet lacking canonical cell wall-derived host-recognition motifs found in bacteria, human-associated archaea Methanosphaera stadtmanae and Methanobrevibacter smithii show immune activity and disease links but remain largely underexplored. Time-resolved RNA-seq in human PBMCs identified an immune program shared with bacterial or viral stimuli across both archaeal species, yet their kinetics diverged, with M. stadtmanae inducing earlier and stronger activation and M. smithii eliciting more gradual responses. Among conserved early-upregulated genes, two classes emerged: Class I was preferentially induced by M. stadtmanae, whereas Class II was similarly induced by both species. To investigate the origin of the Class I/II phenotype, we measured uptake and applied TLR8 inhibition, finding greater early uptake with M. stadtmanae and broad TLR8 dependence across readouts. Consistent with this gene-class separation, ChIP-qPCR showed that M. stadtmanae, but not M. smithii, strongly induced NF-{kappa}B p65 binding at representative Class I promoters, while STAT1/2 binding at representative Class II promoters occurred with both stimuli. Dose-response analyses with RNA inputs established distinct activation thresholds, with Class II at low dose (via STAT1/2) and Class I only at higher dose (via p65). Together, these findings support an input-tuned logic in which archaeal inputs and RNA sensing gate TLR8-dependent immune programs.

immunology↗

bioRxiv2025

JAK/STAT Signaling Governs Airway Epithelial Homeostasis and Stress Resilience in Drosophila

Airway epithelia must maintain barrier integrity while continuously adapting to changing environmental conditions. This requires key signaling pathways in airway epithelia to operate within a tightly controlled functional range. Here, we show that airway epithelial homeostasis in Drosophila depends on balanced JAK/STAT signaling. Basal pathway activity is constitutively present in differentiated epithelial cells and is necessary for cell survival, epithelial integrity and stress resistance. In accordance with this role as a stress responsive regulator in epithelial biology, environmental stressors, including hypoxia, cigarette smoke, and cold exposure, induce JAK/STAT signaling. In contrast, sustained pathway activation is associated with airway remodeling characterized by epithelial thickening, luminal narrowing, and altered cellular organization. Transcriptomic analysis reveals that sustained activation is associated with a coordinated epithelial stress program integrating immune signaling, proteostasis, and metabolic adaptation. Cross-species comparisons with murine and human datasets suggest that key aspects of this response are conserved. Pharmacological inhibition demonstrates that remodeling depends on continued pathway activity and can be partially reversed in vivo. Together, our findings support a model in which airway epithelial homeostasis depends on maintaining JAK/STAT signaling within a defined functional range. This "Goldilocks" principle provides a conceptual framework for understanding how epithelial stress responses are balanced under physiological and pathological conditions. Graphical abstract

cell biology↗

bioRxiv2025

Genomic Insights into Ceftazidime Resistance in Burkholderia pseudomallei: Discovery of A172T Mutation, and Palindromic GC-Rich Repeat Sequences Facilitating penA Duplication and Amplification.

Ceftazidime (CAZ) resistance in Burkholderia pseudomallei, the causative agent of melioidosis, complicates treatment in endemic regions. This study identified a novel A172T mutation and other known penA mutations as critical contributors to CAZ resistance in a large Thai strain collection. Frequent gene duplication and amplification (GDA) of penA, likely driven by Palindromic GC-Rich Repeat Sequences (PGCRRS), highlights the urgent need for rapid diagnostics and optimized treatment strategies to manage this life-threatening disease effectively.

microbiology↗

bioRxiv2024

FoxO factors are essential for maintaining organ homeostasis by acting as stress sensors in airway epithelial cells

Airway epithelia must maintain functional and structural homeostasis despite exposure to diverse environmental stressors. FoxO transcription factors are well suited to this task, acting as integration hubs that translate extrinsic and intrinsic signals into appropriate physiological responses. We show that FoxO factors in Drosophila, mouse, and human airway epithelial cells (AECs) undergo nuclear translocation in response to stressors including hypoxia, temperature, and oxidative stress. In human airway epithelial cell lines, individual hFOXO factors show distinct, cell-type-specific activation patterns. In Drosophila, hypoxia was the only stressor among those tested that triggered a dfoxo-dependent innate immune response. Because Drosophila possesses a single FoxO ortholog, loss-of-function analysis directly demonstrated that dfoxo is required for stress resistance in the airway epithelium. Reduced FoxO expression was similarly observed in mouse models of asthma and in airway samples from asthma patients, paralleling the increased stress sensitivity seen upon FoxO loss in flies. While our data do not establish that reduced FOXO levels cause asthma, they indicate that FoxO-dependent stress pathways are altered in diseased airways across species. Together, these findings support a model in which FoxO coordinates adaptive epithelial stress responses that maintain airway homeostasis under environmental challenge.

physiology↗

bioRxiv2023

Recurrent phases of strict protein limitation inhibit tumor growth and restore lifespan in a Drosophila intestinal cancer model

Diets that restrict caloric or protein intake offer a variety of benefits, including decreasing the incidence of cancer. However, whether such diets pose a substantial therapeutic benefit as auxiliary cancer treatments remains unclear. We determined the effects of severe protein depletion on tumorigenesis in a Drosophila melanogaster intestinal tumor model, using a human RAF gain-of-function allele. Severe and continuous protein restriction significantly reduced tumor growth but resulted in premature death. Therefore, we developed a diet in which short periods of severe protein restriction alternated cyclically with periods of complete feeding. This nutritional regime reduced tumor mass, restored gut functionality, and normalized the lifespan of oncogene-expressing flies to the levels observed in healthy control flies. Furthermore, this diet reduced the chemotherapy-induced stem cell activity associated with tumor recurrence. Transcriptome analysis revealed long-lasting changes in the expression of key genes involved in multiple major developmental signaling pathways. Overall, the data suggest that recurrent severe protein depletion effectively mimics the health benefits of continuous protein restriction, without undesired nutritional shortcomings. This provides seminal insights into the mechanisms of the transcriptomic memory effect required to maintain the positive effects of protein restriction throughout the phases of a full diet.

cancer biology↗

bioRxiv2020

WNT6-ACC2-induced accumulation of triacylglycerol rich lipid droplets is exploited by Mycobacterium tuberculosis

In view of emerging drug-resistant tuberculosis, host directed therapies are urgently needed to improve treatment outcomes with currently available anti-tuberculosis therapies. One option is to interfere with the formation of lipid-laden “foamy” macrophages in the infected host. Here, we provide evidence that WNT6, a member of the evolutionary conserved WNT signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase-2 (ACC2) during pulmonary TB. In addition, we demonstrate that Mycobacterium tuberculosis (Mtb) facilitates its intracellular growth and dissemination in the host by exploiting the WNT6-ACC2 pathway. Using genetic and pharmacological approaches, we show that lack of functional WNT6 or ACC2 significantly reduces intracellular TAG levels, Mtb growth and necrotic cell death of macrophages. In combination with the anti-TB drug isoniazid, pharmacological inhibition of ACC2 improved anti-mycobacterial treatment in vitro and in vivo. Therefore, we propose the WNT6-ACC2 signaling pathway as a promising target for a host-directed therapy to reduce intracellular replication of Mtb by modulating neutral lipid metabolism.Competing Interest StatementDrs. N. Reiling and J. Brandenburg (Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany) have filed a patent application entitled ACC inhibitors as means and methods for treating mycobacterial diseases(WO2018007430A1, patent pending).View Full Text

immunology↗

bioRxiv2020

Balanced JAK/STAT signaling is critical to maintain the functional and structural integrity of the Drosophila respiratory epithelium

Signaling mediated by the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is critical for maintaining cellular and functional homeostasis in the lung. Thus, chronically activated JAK/STAT signaling is causally associated with lung diseases such as lung cancer, asthma, and chronic obstructive pulmonary disease. To elucidate the molecular processes that transform increased JAK/STAT signaling in airway epithelial cells into the known pathological states, we used a highly simplified model system, the fruit fly Drosophila melanogaster. Here, the JAK/STAT pathway is permanently active in almost all airway cells and responds to airborne stressors with increased activity. Silencing of this signaling pathway in epithelial cells resulted in apoptosis. Since the above-mentioned lung diseases are commonly associated with increased JAK/STAT signaling, we assessed this by its ectopic activation in the respiratory epithelium of Drosophila. This intervention triggered cell-autonomous structural changes in epithelial cells. These structural changes included phenotypes associated with asthma, namely, thickening of the epithelium, substantial narrowing of the air-conducting space, and impairment of the secretory epicuticular structure of the tracheae. Pharmacological manipulation of JAK/STAT signaling reversed this pathological phenotype. Transcriptomic analyses revealed that several biological processes were affected, which is consistent with the impairment of junction protein trafficking also observed in this study. These results indicate that balanced JAK/STAT signaling is essential for the functionality of the respiratory epithelium and, by extension, the entire organ. In contrast, chronic overactivation of this signaling leads to massive structural changes that are closely associated with pathologies typical of chronic inflammatory lung diseases. HighlightsO_LIJAK/STAT signaling is active in the entire Drosophila respiratory system in all developmental stages. C_LIO_LIThe signaling pathway is indispensable for the survival of the tracheal cell. C_LIO_LIOveractivation of the signaling has significant effects on tracheal development and also displays a human disease-associated phenotype in Drosophila trachea. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/160929v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1f82913org.highwire.dtl.DTLVardef@150a79corg.highwire.dtl.DTLVardef@2c1130org.highwire.dtl.DTLVardef@11c7cf8_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗