Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2+ macrophages in various disease conditions, and substantial induction of TREM2+ NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2+ macrophages in disease pathogenesis.

The kainate receptor GluK2 mediates cold sensing in mice.

Thermosensors expressed in peripheral somatosensory neurons sense a wide range of environmental temperatures. While thermosensors detecting cool, warm and hot temperatures have all been extensively characterized, little is known about those sensing cold temperatures. Though several candidate cold sensors have been proposed, none has been demonstrated to mediate cold sensing in somatosensory neurons in vivo, leaving a knowledge gap in thermosensation. Here we characterized mice lacking the kainate-type glutamate receptor GluK2, a mammalian homolog of the Caenorhabditis elegans cold sensor GLR-3. While GluK2 knockout mice respond normally to heat and mechanical stimuli, they exhibit a specific deficit in sensing cold but not cool temperatures. Further analysis supports a key role for GluK2 in sensing cold temperatures in somatosensory DRG neurons in the periphery. Our results reveal that GluK2-a glutamate-sensing chemoreceptor mediating synaptic transmission in the central nervous system-is co-opted as a cold-sensing thermoreceptor in the periphery.

A C. elegans neuron both promotes and suppresses motor behavior to fine tune motor output.

How neural circuits drive behavior is a central question in neuroscience. Proper execution of motor behavior requires precise coordination of many neurons. Within a motor circuit, individual neurons tend to play discrete roles by promoting or suppressing motor output. How exactly neurons function in specific roles to fine tune motor output is not well understood. In C. elegans, the interneuron RIM plays important yet complex roles in locomotion behavior. Here, we show that RIM both promotes and suppresses distinct features of locomotion behavior to fine tune motor output. This dual function is achieved via the excitation and inhibition of the same motor circuit by electrical and chemical neurotransmission, respectively. Additionally, this bi-directional regulation contributes to motor adaptation in animals placed in novel environments. Our findings reveal that individual neurons within a neural circuit may act in opposing ways to regulate circuit dynamics to fine tune behavioral output.

Sensing of sound pressure gradients by C. elegans drives phonotaxis behavior.

Despite lacking ears, the nematode C. elegans senses airborne sound and engages in phonotaxis behavior, enabling it to locate and avoid sound sources.1 How worms sense sound, however, is not well understood. Here, we report an interesting observation that worms respond only to sounds emitted by small but not large speakers, indicating that they preferentially respond to localized sound sources. Notably, sounds emitted by small speakers form a sharp sound pressure gradient across the worm body, while sounds from large speakers do not, suggesting that worms sense sound pressure gradients rather than absolute sound pressure. Analysis of phonotaxis behavior, sound-evoked skin vibration, and sound-sensitive neuron activities further support this model. We suggest that the ability to sense sound pressure gradients provides a potential mechanism for worms to distinguish sounds generated by their predators, which are typically small animals, from those produced by large animals or background noise. As vertebrate cochlea and some insect ears can also detect sound pressure gradients, our results reveal that sensing of sound pressure gradients may represent a common mechanism in auditory sensation across animal phyla. VIDEO ABSTRACT.

Mechanosensitive GPCRs and ion channels in shear stress sensing.

As a universal mechanical cue, shear stress plays essential roles in many physiological processes, ranging from vascular morphogenesis and remodeling to renal transport and airway barrier function. Disrupted shear stress is commonly regarded as a major contributor to various human diseases such as atherosclerosis, hypertension, and chronic kidney disease. Despite the importance of shear stress in physiology and pathophysiology, our current understanding of mechanosensors that sense shear stress is far from complete. An increasing number of candidate mechanosensors have been proposed to mediate shear stress sensing in distinct cell types, including G protein-coupled receptors (GPCRs), G proteins, receptor tyrosine kinases, ion channels, glycocalyx proteins, and junctional proteins. Although multiple types of mechanosensors might be able to convert shear stress into downstream biochemical signaling events, in this review, we will focus on discussing the mechanosensitive GPCRs (angiotensin II type 1 receptor, GPR68, histamine H1 receptor, adhesion GPCRs) and ion channels (Piezo, TRP) that have been reported to be directly activated by shear stress.

Electroreception: Worms leap to insects for dispersal.

Electroreception is employed by some fishes to locate prey or predators. However, why the nematode Caenorhabditis elegans senses electric fields is unclear. A new study shows that electroreception helps these microscopic worms to attach themselves to insects for transportation.

Cytoplasmic and mitochondrial aminoacyl-tRNA synthetases differentially regulate lifespan in Caenorhabditis elegans.

Reducing the rate of translation promotes longevity in multiple organisms, representing a conserved mechanism for lifespan extension. Aminoacyl-tRNA synthetases (ARSs) catalyze the loading of amino acids to their cognate tRNAs, thereby playing an essential role in translation. Mutations in ARS genes are associated with various human diseases. However, little is known about the role of ARSs in aging, particularly whether and how these genes regulate lifespan. Here, using Caenorhabditis elegans as a model, we systematically characterized the role of all three types of ARS genes in lifespan regulation, including mitochondrial, cytoplasmic, and cyto-mito bifunctional ARS genes. We found that, as expected, RNAi knockdown of mitochondrial ARS genes extended lifespan. Surprisingly, knocking down cytoplasmic or cyto-mito bifunctional ARS genes shortened lifespan, though such treatment reduced the rate of translation. These results reveal opposing roles of mitochondrial and cytoplasmic ARSs in lifespan regulation, demonstrating that inhibiting translation may not always extend lifespan.

Chemosensation: Corollary discharge filters out self-generated chemical cues.

Corollary discharge allows organisms to discriminate external sensory inputs from self-generated cues. However, the underlying synaptic and molecular mechanisms are not well understood. A new study has identified a tyraminergic corollary discharge signal that extrasynaptically modulates chemosensory neurons in Caenorhabditis elegans.

A cilia-independent function of BBSome mediated by DLK-MAPK signaling in C. elegans photosensation.

Bardet-Biedl syndrome (BBS) is a genetic disorder that affects primary cilia. BBSome, a protein complex composed of eight BBS proteins, regulates the structure and function of cilia, and its malfunction causes BBS in humans. Here, we report a cilia-independent function of BBSome. To identify genes that regulate the C. elegans photoreceptor protein LITE-1 in ciliated ASH photosensory neurons, we performed a genetic screen and isolated bbs mutants. Functional analysis revealed that BBSome regulates LITE-1 protein stability independently of cilia. Through another round of genetic screening, we found that this cilia-independent function of BBSome is mediated by DLK-MAPK signaling, which acts downstream of BBSome to control LITE-1 stability via Rab5-mediated endocytosis. BBSome exerts its function by regulating the expression of DLK. BBSome also regulates the expression of LZK, a mammalian DLK in human cells. These studies identify a cilia-independent function of BBSome and uncover DLK as an evolutionarily conserved BBSome effector.

Thermosensation: How a human-infective nematode finds its host.

The parasitic nematode Strongyloides stercoralis locates human hosts via thermal cues through unknown neural mechanisms. A new study finds that the heat-sensing neuron AFD mediates attraction to human body heat. Interestingly, this neuron also mediates thermotaxis in the nematode C. elegans.

The nematode C. elegans senses airborne sound.

Unlike olfaction, taste, touch, vision, and proprioception, which are widespread across animal phyla, hearing is found only in vertebrates and some arthropods. The vast majority of invertebrate species are thus considered insensitive to sound. Here, we challenge this conventional view by showing that the earless nematode C. elegans senses airborne sound at frequencies reaching the kHz range. Sound vibrates C. elegans skin, which acts as a pressure-to-displacement transducer similar to vertebrate eardrum, activates sound-sensitive FLP/PVD neurons attached to the skin, and evokes phonotaxis behavior. We identified two nAChRs that transduce sound signals independently of ACh, revealing an unexpected function of nAChRs in mechanosensation. Thus, the ability to sense airborne sound is not restricted to vertebrates and arthropods as previously thought, and might have evolved multiple times independently in the animal kingdom, suggesting convergent evolution. Our studies also demonstrate that animals without ears may not be presumed to be sound insensitive.

TRP channels: Intestinal bloating TRiPs up pathogen avoidance.

Transient receptor potential (TRP) channels are expressed in many nonneural tissues where their functions are not well known. Using C. elegans as a model, a new study demonstrated that colonization of the Gram-positive pathogenic bacteria E. faecalis in the intestine causes intestinal distention. Two TRPM channels sense such intestinal distension to trigger fast pathogen avoidance behavior, thereby limiting pathogen infection. This work signifies the novel role of TRP channels in gut physiology and pathogen defense.

Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal.

The role of food nutrients in mediating the positive effect of dietary restriction (DR) on longevity has been extensively characterized, but how non-nutrient food components regulate lifespan is not well understood. Here, we show that food-associated odors shorten the lifespan of C. elegans under DR but not those fed ad libitum, revealing a specific effect of food odors on DR-mediated longevity. Food odors act on a neural circuit comprising the sensory neurons ADF and CEP, and the interneuron RIC. This olfactory circuit signals the gut to suppress DR-mediated longevity via octopamine, the invertebrate homolog of norepinephrine, by regulating the energy sensor AMPK through a Gq-PLCß-CaMKK-dependent mechanism. In mouse primary cells, we find that norepinephrine signaling regulates AMPK through a similar mechanism. Our results identify a brain-gut axis that regulates DR-mediated longevity by relaying olfactory information about food abundance from the brain to the gut.

Temperature Sensation: From Molecular Thermosensors to Neural Circuits and Coding Principles.

Temperature is a universal cue and regulates many essential processes ranging from enzymatic reactions to species migration. Due to the profound impact of temperature on physiology and behavior, animals and humans have evolved sophisticated mechanisms to detect temperature changes. Studies from animal models, such as mouse, Drosophila, and C. elegans, have revealed many exciting principles of thermosensation. For example, conserved molecular thermosensors, including thermosensitive channels and receptors, act as the initial detectors of temperature changes across taxa. Additionally, thermosensory neurons and circuits in different species appear to adopt similar logic to transduce and process temperature information. Here, we present the current understanding of thermosensation at the molecular and cellular levels. We also discuss the fundamental coding strategies of thermosensation at the circuit level. A thorough understanding of thermosensation not only provides key insights into sensory biology but also builds a foundation for developing better treatments for various sensory disorders.

Regulation of photosensation by hydrogen peroxide and antioxidants in C. elegans.

The eyeless C. elegans exhibits robust phototaxis behavior in response to short-wavelength light, particularly UV light. C. elegans senses light through LITE-1, a unique photoreceptor protein that belongs to the invertebrate taste receptor family. However, it remains unclear how LITE-1 is regulated. Here, we performed a forward genetic screen for genes that when mutated suppress LITE-1 function. One group of lite-1 suppressors are the genes required for producing the two primary antioxidants thioredoxin and glutathione, suggesting that oxidization of LITE-1 inhibits its function. Indeed, the oxidant hydrogen peroxide (H2O2) suppresses phototaxis behavior and inhibits the photoresponse in photoreceptor neurons, whereas other sensory behaviors are relatively less vulnerable to H2O2. Conversely, antioxidants can rescue the phenotype of lite-1 suppressor mutants and promote the photoresponse. As UV light illumination generates H2O2, we propose that upon light activation of LITE-1, light-produced H2O2 then deactivates LITE-1 to terminate the photoresponse, while antioxidants may promote LITE-1's recovery from its inactive state. Our studies provide a potential mechanism by which H2O2 and antioxidants act synergistically to regulate photosensation in C. elegans.

C. elegans: a sensible model for sensory biology.

From Sydney Brenner's backyard to hundreds of labs across the globe, inspiring six Nobel Prize winners along the way, Caenorhabditis elegans research has come far in the past half century. The journey is not over. The virtues of C. elegans research are numerous and have been recounted extensively. Here, we focus on the remarkable progress made in sensory neurobiology research in C. elegans. This nematode continues to amaze researchers as we are still adding new discoveries to the already rich repertoire of sensory capabilities of this deceptively simple animal. Worms possess the sense of taste, smell, touch, light, temperature and proprioception, each of which is being studied in genetic, molecular, cellular and systems-level detail. This impressive organism can even detect less commonly recognized sensory cues such as magnetic fields and humidity.

Short-term enhancement of motor neuron synaptic exocytosis during early aging extends lifespan in Caenorhabditis elegans.

IMPACT STATEMENT: The functional decline of motor activity is a common feature in almost all aging animals that leads to frailty, loss of independence, injury, and even death in the elderly population. Thus, understanding the molecular mechanism that drives the initial stage of this functional decline and developing strategies to increase human healthspan and even lifespan by targeting this process would be of great interests to the field. In this study, we found that by precisely targeting the motor neurons to potentiate its synaptic releases either genetically or pharmacologically, we can not only delay the functional aging at NMJs but also slow the rate of aging at the organismal level. Most importantly, we have demonstrated that a critical window of time, that is the early stage of NMJs functional decline, is required for the beneficial effects. A short-term treatment within this time period is sufficient to extend the animals' lifespan.

Adrenergic-Independent Signaling via CHRNA2 Regulates Beige Fat Activation.

Maintaining energy homeostasis upon environmental challenges, such as cold or excess calorie intake, is essential to the fitness and survival of mammals. Drug discovery efforts targeting ß-adrenergic signaling have not been fruitful after decades of intensive research. We recently identified a new beige fat regulatory pathway mediated via the nicotinic acetylcholine receptor subunit CHRNA2. Here, we generated fat-specific Chrna2 KO mice and observed thermogenic defects in cold and metabolic dysfunction upon dietary challenges caused by adipocyte-autonomous regulation in vivo. We found that CHRNA2 signaling is activated after acute high fat diet feeding and this effect is manifested through both UCP1- and creatine-mediated mechanisms. Furthermore, our data suggested that CHRNA2 signaling may activate glycolytic beige fat, a subpopulation of beige adipocytes mediated by GABPα emerging in the absence of ß-adrenergic signaling. These findings reveal the biological significance of the CHRNA2 pathway in beige fat biogenesis and energy homeostasis.

Parallel Processing of Two Mechanosensory Modalities by a Single Neuron in C. elegans.

Neurons convert synaptic or sensory inputs into cellular outputs. It is not well understood how a single neuron senses, processes multiple stimuli, and generates distinct neuronal outcomes. Here, we describe the mechanism by which the C. elegans PVD neurons sense two mechanical stimuli: external touch and proprioceptive body movement. These two stimuli are detected by distinct mechanosensitive DEG/ENaC/ASIC channels, which trigger distinct cellular outputs linked to mechanonociception and proprioception. Mechanonociception depends on DEGT-1 and activates PVD's downstream command interneurons through its axon, while proprioception depends on DEL-1, UNC-8, and MEC-10 to induce local dendritic Ca2+ increase and dendritic release of a neuropeptide NLP-12. NLP-12 directly modulates neuromuscular junction activity through the cholecystokinin receptor homolog on motor axons, setting muscle tone and movement vigor. Thus, the same neuron simultaneously uses both its axon and dendrites as output apparatus to drive distinct sensorimotor outcomes.