de Graaf, D. M. | bioRxiv Science

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

IL-38 regulates intestinal stem cell homeostasis by inducing WNT signaling and beneficial IL-1beta secretion

The IL-1 Family member IL-38 has been characterized primarily as an anti-inflammatory cytokine in human and mouse models of systemic diseases. Here, we examined the role of IL-38 in the murine small intestine (SI). Immunostaining of SI revealed that IL-38 expression partially confines to intestinal stem cells. Cultures of intestinal organoids reveal IL-38 functions as a growth factor by increasing organoid size via inducing WNT3a. In contrast, organoids from IL-38 deficient mice develop more slowly. This reduction in size is likely due to downregulation of intestinal stemness markers (i.e., Fzd5, Ephb2, Olfm4) expression compared with wild type organoids. IL-38 binding to IL-1R6 is postulated to recruit the co-receptor IL-1R9. Therefore, to analyze the molecular mechanisms of IL-38 signaling, we also examined organoids from IL-1R9 deficient mice. Unexpectedly, these organoids, although significantly smaller than wild type, respond to IL-38, suggesting that IL-1R9 is not involved in IL-38 signaling in the stem cell crypt. Nevertheless, silencing of IL-1R6 disabled the organoid response to the growth property of IL-38, thus suggesting IL-1R6 as the main receptor used by IL-38 in the crypt compartment. In organoids from wild type mice, IL-38 stimulation induced low concentrations of IL-1{beta} which contribute to organoid growth. However, high concentrations of IL-1{beta} have detrimental effects on the cultures that were prevented by treatment with recombinant IL-38. Overall, our data demonstrate an important regulatory function of IL-38 as a growth factor, and as an anti-inflammatory molecule in the SI, maintaining homeostasis. SignificanceThe IL-1 family member IL-38 has been characterized primarily as an anti-inflammatory cytokine for systemic diseases. Here we describe a fundamental role of IL-38 in driving intestinal stem cell differentiation through the upregulation of WNT3a and IL-1{beta}. Our findings reveal a dual role of IL-38 in regulating intestinal functions; (a) in resting conditions IL-38 maintains intestinal homeostasis, driving WNT3a production and organoid budding, whereas (b) in highly inflamed conditions, IL-38 contributes to proper recovery, by exerting anti-inflammatory activities. Thus, we demonstrate a pivotal role of IL-38 in driving tissue turnover and maintenance of homeostasis in intestinal health.

cell biology↗