Biology subjects

Kerner, Z.

Publications and source records attributed to Kerner, Z..

5 recordsLinked to original sources

bioRxiv2026

GFRAL neurons remodel intestinal structure and type 2 immunity

The brain has emerged as a key regulator of immune functions, but the underlying neural mechanisms remain poorly understood. Here we show that brainstem GFRAL-expressing neurons prime type 2 immunity and shape intestinal epithelial structure in mice. Type 2 inflammation results in activation of GFRAL neurons and potentiation of their excitatory synaptic inputs. Enhancing GFRAL neuron excitability is sufficient to remodel intestinal type 2 immunity through a polysynaptic vagal brain-gut circuit, expanding tuft and goblet cell populations and increasing intestinal type 2 cytokine expression; while inhibiting GFRAL neurons leads to largely opposite changes. Accordingly, manipulating GFRAL neuron function reshapes intestinal structure and pathophysiology in food allergy, helminth infection and colitis models. Thus, GFRAL neurons orchestrate type 2 immune responses to facilitate recovery from intestinal diseases.

neuroscience↗

bioRxiv2026

Eosinophil-epithelial interactions mediate protective intestinal remodeling during food allergy

Food allergies are associated with progressive gastrointestinal symptoms driven by exacerbated mucosal type-2 immunity. Here, we investigated whether cellular interactions between the gut epithelium and innate immune cells regulate the severity of allergic symptoms in mice. Using the BALB/c OVA-alum food allergy model, we observed that repeated oral allergen challenges remodel the gut epithelium, expanding tuft cells, while shifting the intestinal stem cell niche toward a fetal-like repair state. Using uLIPSTIC, we systematically characterized in vivo immune-epithelial interactions and found that eosinophils and mast cells directly interact with intestinal epithelial cells (iECs) in an allergen challenge-dependent manner. Epithelial subset-specific uLIPSTIC provided further resolution and revealed that eosinophils and mast cells contact enteroendocrine cells and Paneth cells in a regionally compartmentalized manner. Allergic challenge was associated with rapid eosinophil migration towards the crypts and modulation of iEC differentiation. Depletion of eosinophils using two independent approaches reversed key markers of food allergy-associated epithelial remodeling, while exacerbating allergic diarrhea and mortality from anaphylactic shock. These findings establish eosinophils as orchestrators of protective epithelial remodeling in food allergies.

immunology↗

bioRxiv2024

Neuronal substance-P drives breast cancer growth and metastasis via an extracellular RNA/TLR7 axis

Increased tumour innervation is associated with adverse survival outcomes in multiple cancers1-4. To better understand the mechanisms underlying this, we studied the impact of innervation on breast cancer metastatic progression. Metastatic mammary tumours of mice were substantially more innervated than non-metastatic isogenic tumours. Three dimensional co-cultures and in vivo models revealed that sensory dorsal root ganglion (DRG) neurons enhanced the growth, invasion, and systemic dissemination of cancer cells--thereby driving breast cancer metastasis. By in vitro screening of neuropeptides known to be secreted by DRG neurons, we identified substance-P (SP) as a mediator of these pro-metastatic functions. Neuronal SP signaled through tumoural tachykinin receptors (TACR1) to drive single-stranded RNA (ssRNA) secretion from cancer cells. Extracellular RNA acted on tumoural TLR7 receptors to activate an autocrine pro-metastatic gene expression program. In support of these findings, patient tumours with increased SP expression exhibited higher rates of lymph node metastasis. Additionally, this SP/ssRNA induced Tlr7 gene expression signature associated with reduced breast cancer survival outcomes in two independent patient cohorts. Finally, therapeutic targeting of this neuro-cancer axis with the TACR1 antagonist aprepitant, an approved anti-nausea drug, suppressed breast cancer metastasis in multiple mouse models. Our findings reveal multiple aspects of metastatic progression to be regulated by neurons via a therapeutically targetable neuropeptide/extracellular RNA sensing axis.

cancer biology↗

bioRxiv2020

Microbiota-modulated enteric neuron translational profiling uncovers a CART+ glucoregulatory subset

Microbial density and diversity increase towards the distal intestine, affecting tissue physiology, metabolism, and function of both immune and nervous systems. Intrinsic enteric-associated neurons (iEAN) continuously monitor and modulate intestinal functions, including nutrient absorption and motility. Through molecular, anatomic and functional approaches, we characterized the influence of the microbiota on iEAN. We found that iEAN are functionally adapted to the intestinal segment they occupy, with a stronger microbiota influence on distal intestine neurons. Chemogenetic characterization of microbiota-influenced iEAN identified a subset of viscerofugal CART+ neurons, enriched in the distal intestine, able to modulate feeding through insulin-glucose levels. Retro- and anterograde tracing revealed that CART+ viscerofugal neurons send axons to the gut sympathetic ganglion and are synaptically connected to the liver and pancreas. Our results demonstrate a region-specific adaptation of enteric neurons and indicate that specific iEAN subsets are capable of regulating host physiology independently from the central nervous system. One Sentence SummaryMicrobes impact regionally defined intrinsic enteric neuron translatomes, including a novel CART+ glucoregulatory viscerofugal population.

neuroscience↗

bioRxiv2019

Microbiota imprint gut-intrinsic neuronal programming and sympathetic activity

Microbial density and diversity increases from proximal to distal regions of the intestine, affecting tissue physiology, metabolism, and function of the immune and nervous systems. Both intrinsic and extrinsic enteric-associated neurons (EAN) continuously monitor and modulate homeostatic intestinal functions, including nutrient absorption and motility. However, a systemic and circuit-based link between gut microbes and the nervous system has yet to be established. Through a combination of molecular, anatomic and functional approaches, we characterized the influence of the microbiota on EAN. We found that intrinsic EAN are functionally adapted to the specific intestinal region they occupy in a microbiota-dependent manner. Furthermore, we observed that gut-extrinsic sympathetic neurons are hyperactivated in the absence of microbes, while the production of butyrate is sufficient to suppress sympathetic activity. Finally, retrograde polysynaptic neuronal tracing from the intestinal wall revealed that brainstem GABAergic neurons are a potential central hub for modulation of gut-specific sympathetic neurons. These results reveal that commensal microbiota imprint gut-intrinsic neuronal gene programs and control extrinsic sympathetic activity through a metabolite-mediated gut-brain circuit.

neuroscience↗