Biology subjects

Bertin, J.

Publications and source records attributed to Bertin, J..

5 recordsLinked to original sources

bioRxiv2025

FL/FLT3 signaling enhances mechanical pain hypersensitivity through Interleukin-1 beta (IL-1β) in male mice

Fms-like tyrosine kinase 3 (FLT3) plays a critical role in chronic pain through its ligand FL, a cytokine that triggers mechanical pain hypersensitivity. However, the underlying molecular mechanisms remain unclear. Here, we investigate the potential interplay between FL and IL-1{beta} a key cytokine in DRG neurons sensitization and mechanical hyperalgesia through both in vitro and in vivo approaches. ELISA assays reveal that intrathecal FL administration significantly increases IL-1{beta} protein levels in both the DRG and dorsal spinal cord of mice, beginning four hours post-injection. Using video microscopy and [Ca2+]i fluorescence imaging in primary DRG neuron cultures, we demonstrate that FL potentiation of TRPV1 receptor responses to capsaicin is partially mediated by IL-1{beta} signalling, as evidenced by a significant reduction in this potentiation in the presence of the IL-1 receptor antagonist, IL-1Ra. Furthermore, FLT3-driven acute mechanical pain hypersensitivity in vivo is reduced both by prior administration of IL-1Ra and in IL-1 receptor knockout mice. Importantly, IL-1{beta}-induced mechanical pain hypersensitivity remains independent of FLT3 signalling as shown in Flt3 knockout mice. Collectively our findings expand the understanding of neuro-immune interactions by demonstrating a potential functional link between FL/FLT3 and IL-1{beta}/IL-1R signalling in nociceptive processing. HighlightsCytokines are known to engage in complex interactions and regulate each other FL increases IL-1{beta} in DRG and DSC within 4h, but IL-1{beta} does not affect FL levels FL modulates capsaicin-induced Ca2+ influx via IL-1{beta}/IL-1R signalling in DRG neurons IL-1R inhibition delays or abolishes FL-induced mechanical hypersensitivity in vivo Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/648037v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@11cfa96org.highwire.dtl.DTLVardef@187ac2borg.highwire.dtl.DTLVardef@387234org.highwire.dtl.DTLVardef@1d1c058_HPS_FORMAT_FIGEXP M_FIG The timeline of the experimental design and the graphical abstract were created with BioRender.com C_FIG

neuroscience↗

bioRxiv2024

Raver1 links Ripk1 RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance

Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis and inflammation. Here we discovered a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality, and the subsequent caspase-8-dependent inflammatory cell death. Macrophages from Raver1-deficient mice exhibit altered splicing of Ripk1, accompanied by diminished cell death and reduced activation of caspase-8, Gasdermin D and E, caspase-1, as well as decreased interleukin-18 (IL-18) and IL-1{beta} production. These effects were triggered by Yersinia bacteria, or by restraining TAK1 or IKK{beta} in the presence of LPS, TNF family members, or IFN{gamma}. Consequently, animals lacking Raver1 showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes. SignificanceCaspase-8 and the kinase RIPK1 are at focal points of several inflammation and cell death pathways. Thus, a careful regulation of their actions is needed. Our work identifies the RNA splicing factor Raver1 as a critical factor directing the splicing of Ripk1 in order to modulate RIPK1/caspase-8-driven pyroptosis, apoptosis and inflammation. Raver1 is central for macrophage responses to Yersinia bacteria, initiated after blockade of kinases TAK1 and IKK, measured as activation of RIPK1, caspase-8, Gasdermin D, caspase-3, IL-1{beta} and IL-18. Importantly, Raver1 is necessary for host resistance to Yersinia infection in vivo. We propose that Raver1 is key for correct tuning of RIPK1-caspase-8 dependent processes.

immunology↗

bioRxiv2024

Alternative cGAS signaling promotes Herpes simplex encephalitis

During infection, foreign DNA is sensed by cyclic GMP-AMP synthase (cGAS) leading to the production of cGAMP, STING-dependent type I interferon and proinflammatory cytokine expression, and autophagy. To prevent a response to self-DNA, cGAS activity is tightly regulated. Dysregulation of cGAS underpins interferonopathies, such as Aicardi-Goutieres syndrome, as well as Lupus and neurodegenerative diseases like Parkinsons disease. Thus, cGAS and its product cGAMP are therapeutic targets. However, if cGAS functions independently of cGAMP signaling is undefined. Here, we identified an alternative signaling pathway that cGAS engages independent of cGAMP synthesis. We demonstrate that alternative cGAS signaling promotes hyperexpression of CXCL1 and enhanced neutrophil recruitment that facilitates viral dissemination during herpes simplex encephalitis. Our study is the first report of an alternative cGAS response independent of cGAMP highlighting a previously uncharacterized scaffold function for cGAS.

immunology↗

bioRxiv2024

MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. Here, we show that MALT1 plays a key role in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-{kappa}B signaling axis within macrophages, leading to macrophage migration and polarization toward an immunosuppressive phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage "M1-like" phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in increased immuno-reactivity of GBM-associated macrophages and reduced GBM tumor growth. Further, the addition of MALT1 inhibitor to temozolomide reduces immunosuppression in the tumor microenvironment, which may enhance the efficacy of this standard-of-care chemotherapeutic. Together, our findings suggest that MALT1 protease inhibition represents a promising macrophage-targeted immunotherapeutic strategy for the treatment of GBM. Graphical abstract. O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/614808v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@18c969eorg.highwire.dtl.DTLVardef@f48f0dorg.highwire.dtl.DTLVardef@1dbbbb1org.highwire.dtl.DTLVardef@ff8237_HPS_FORMAT_FIGEXP M_FIG The effects of tumor cell-induced CARD9-BCL10-MALT1 (CBM) activation (left) and MALT1 protease inhibition (right) on GBM associated macrophages in the tumor microenvironment. Cartoon of cellular components of a GBM tumor with an immunosuppressive TME characterized by "M2-like macrophages" (left) and conversion to a more immune-reactive tumor microenvironment characterized by "M1-like macrophages and increased effector T-cells (right) as a result of MALT1 protease inhibition. C_FIG

cancer biology↗

bioRxiv2023

FLT3 signaling inhibition preserves opioid analgesia while abrogating tolerance and hyperalgesia

Opioid analgesia is counteracted on chronic use by tolerance and hyperalgesia inducing dose escalation and life-threatening overdoses. Mu opiate receptors (MOR) expressed in primary sensory neurons were recently found to control tolerance and hyperalgesia, but the underlying mechanisms remained elusive. Here we show that genetic inactivation of fms-like tyrosine kinase receptor 3 (FLT3) receptor in sensory neurons abrogates morphine tolerance and hyperalgesia by preventing MOR-induced hyperactivation of the cAMP signaling pathway and subsequent excitatory adaptive processes. Moreover, the specific FLT3 inhibitor BDT001 potentiates morphine analgesia in acute and chronic pain models, without aggravating morphine adverse effects, and reverses tolerance and hyperalgesia once installed. Thus, FLT3 appears as a key regulator of the MOR signaling pathway and its pharmacological blockade shows promise to enhance chronic opioid analgesic efficacy.

neuroscience↗