Biology subjects

Prochnicki, T.

Publications and source records attributed to Prochnicki, T..

4 recordsLinked to original sources

bioRxiv2026

Local albumin excess exacerbates Candida albicans-induced inflammasome activation underlying the immunopathology of vulvovaginal candidiasis.

Vulvovaginal candidiasis (VVC) is a mucosal yeast infection where symptoms are driven by inflammatory responses. The onset of VVC is instigated by the yeast Candida albicans, but the underlying causes of disease-driving hyperinflammation remains incompletely resolved. We found that vaginal albumin concentrations are higher in women with recurrent VVC and during VVC in mice. These albumin levels correlated with inflammatory cytokines in vaginal lavages. While the abundance of this serum protein in the vagina can represent a hallmark of inflammation-induced vascular permeability, we reveal molecular mechanisms by which albumin also drives inflammation. It increased NLRP3 inflammasome activation in human macrophages elicited by C. albicans. Albumin induced fungal adaptations that increased resistance to macrophage-mediated clearance. Further it increased the expression of fungal secreted aspartic protease 1, which we identified as the effector driving inflammasome activation. Moreover, neutrophils show impaired effectivity in clearing C. albicans in presence of albumin. Collectively, vaginal albumin may not only be a consequence of inflammation of the vaginal mucosa, but also can drive hyperinflammatory responses that underlie immunopathology in VVC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/700771v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@f13fd5org.highwire.dtl.DTLVardef@95e58aorg.highwire.dtl.DTLVardef@11104dforg.highwire.dtl.DTLVardef@56e9be_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1{beta} release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1{beta} release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimers disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimers disease, providing new mechanistic insight into the biology of neuroinflammation.

neuroscience↗

bioRxiv2020

Sensing soluble uric acid by Naip1-Nlrp3 platform

The immune system can recognize microbes and sterile tissue damage. Among the damage-associated molecular patterns (DAMPs), uric acid is considered a major component which can trigger inflammation. It represents a breakpoint in the evolutionary history of humans as our ancestors lost the uricase gene, the enzyme responsible for its cleavage. High soluble uric acid (sUA) concentration is able to increase IL-1{beta} in murine, but not human macrophages. We observed that sUA increased the mRNA expression of Naip1 in murine macrophages, and, therefore, we hypothesized that the recognition of sUA can be made by a Naip1-Nlrp3 inflammasome platform. Additionally, we used genome-wide transcriptome analysis, functional analyses and structural modeling predictions and observed that virus-transduction of murine Naip1 into human macrophages induced IL-1{beta} after sUA stimulus, besides leading to fatty acid production and an inflammation-related response. Moreover, pharmacologic inhibition and genetic loss of Nlrp3 led to decreased IL-1{beta} production upon sUA stimulus. Surface plasmon resonance and quartz crystal microbalance showed that sUA is able to interact with Naip1. Naip could be a lost receptor for sUA in the evolutionary process and a better understanding of the immune modulatory function of sUA could lead to design rational novel anti-hyperuricemic therapies.

immunology↗

bioRxiv2019

Platelets fuel the inflammasome activation of innate immune cells

The inflammasomes control the bioactivity of pro-inflammatory cytokines of the interleukin (IL)-1 family. The inflammasome assembled by NLRP3 has been predominantly studied in homogenous cell populations in vitro, neglecting the influence of cellular interactions that occur in vivo. Here, we show that platelets, the second most abundant cells in the blood, boost the inflammasome capacity of human macrophages and neutrophils, and are critical for IL-1 production by monocytes. Platelets license NLRP3 transcription, thereby enhancing ASC nucleation, caspase-1 activity, and IL-1{beta} maturation. Platelet depletion attenuated LPS-induced IL-1{beta} in vivo, and platelet counts correlate with plasma concentrations of IL-1{beta} in malaria patients. Furthermore, a platelet gene signature was enriched among the highest expressed transcripts in IL-1{beta}-driven autoinflammatory diseases. The platelet-mediated enhancement of inflammasome activation was independent of cell-to-cell contacts, platelet-derived lipid mediators, purines, nucleic acids and a host of platelet cytokines, and involved the triggering of calcium sensing receptors on macrophages by a calcium-dependent protein commonly released by platelets and megakaryocytes. Finally, we report that platelets provide an additional layer of regulation of inflammasomes in vivo.

immunology↗