Biology subjects

Ricci, R.

Publications and source records attributed to Ricci, R..

3 recordsLinked to original sources

bioRxiv2023

KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation

Immune cells sense the microenvironment to fine-tune their inflammatory responses. Patients with cryopyrin associated periodic syndrome (CAPS), caused by mutations in the NLRP3 gene, develop auto-inflammation triggered by non-antigenic, e.g. environmental cues. However, the underlying mechanisms are poorly understood. Here, we uncover that KCNN4, a calcium-activated potassium channel, links PIEZO-mediated mechanotransduction to NLRP3 inflammasome activation. Yoda1, a PIEZO1 agonist, lowers the threshold for NLRP3 inflammasome activation. PIEZO-mediated sensing of stiffness and shear stress increases NLRP3-dependent inflammation. Myeloid-specific deletion of PIEZO1/2 protects mice from gouty arthritis. Activation of PIEZO1 triggers calcium influx, which activates KCNN4 to evoke potassium efflux promoting NLRP3 inflammasome activation. Activation of PIEZO signaling is sufficient to activate the inflammasome in cells expressing CAPS-causing NLRP3 mutants via KCNN4. Finally, pharmacologic inhibition of KCNN4 alleviates auto-inflammation in CAPS patient cells and in CAPS-mimicking mice. Thus, PIEZO-dependent mechanical inputs augment inflammation in NLRP3-dependent diseases including CAPS. One Sentence SummaryPIEZO-mediated mechanotransduction stimulates KCNN4-dependent potassium efflux to potentiate NLRP3 inflammasome activation.

immunology↗

bioRxiv2023

Medial prefrontal cortex stimulation abolishes implicit reactions to threats and prevents the return of fear

Down-regulating emotional overreactions toward threats is fundamental for developing treatments for anxiety and post-traumatic disorders. The prefrontal cortex (PFC) is critical for top-down modulatory processes, and despite previous studies adopting repetitive Transcranial Magnetic Stimulation (rTMS) over this region provided encouraging results in enhancing extinction, no studies have hitherto explored the effects of stimulating the medial PFC (mPFC) on threat memory and generalization. Here we showed that rTMS applied before threat memory retrieval abolishes implicit reactions to learned and novel stimuli in humans. These effects were not due to inhibition of electrodermal reactivity and enduringly persisted one week later in the absence of rTMS. No effects were detected on explicit recognition. Critically, we observed stronger attenuation of defensive responses in subjects stimulated over the mPFC than the dlPFC. Our findings uncover a prefrontal region whose modulation can permanently hamper implicit reactions to learned dangers, representing an advance to long-term deactivating overreactions to threats.

neuroscience↗

bioRxiv2021

CaMK1D signaling in AgRP neurons promotes ghrelin-mediated food intake

Hypothalamic AgRP/NPY neurons are key players in the control of feeding behavior. Ghrelin, a major hormone released under fasting conditions, activates orexigenic AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signaling mechanisms in AgRP/NPY neurons remain poorly defined. Here we demonstrate that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated in hypothalamus upon ghrelin stimulation and acts in AgRP neurons to promote ghrelin-dependent food intake. Global CaMK1D knockout mice are resistant to the orexigenic action of ghrelin, gain less body weight and are protected against high-fat diet-induced obesity. Deletion of CaMK1D in AgRP but not in POMC neurons is sufficient to recapitulate above phenotypes. Lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY as well as the amount of AgRP fiber projections to the Paraventricular nucleus (PVN), while electrical activity of AgRP neurons and 5 AMP-activated protein kinase (AMPK) signaling are unaffected. Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons. HighlightsO_LIWhole-body deletion of CaMK1D in mice reduces food intake, ghrelin sensitivity and protects against obesity. C_LIO_LIAgRP/NPY neuron-specific deletion of CaMK1D reduces food intake, ghrelin sensitivity, energy expenditure and protects against obesity. C_LIO_LICaMK1D is dispensable for ghrelin-stimulated electrical activity of AgRP neurons and hypothalamic AMPK signaling. C_LIO_LICaMK1D controls phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP and NPY. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=174 HEIGHT=200 SRC="FIGDIR/small/471546v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@40d7d7org.highwire.dtl.DTLVardef@11a8c64org.highwire.dtl.DTLVardef@1f6fad3org.highwire.dtl.DTLVardef@1cd5581_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗