Ranfley, H. | Search bioRxiv

bioRxiv2025

NLRP1 Shapes Immune and Inflammatory Signatures in Human Melanoma but Not in Mouse Models

Inflammasomes are multiprotein complexes that activate pro-caspase-1, leading to the maturation of the pro-inflammatory cytokines IL-1{beta} and IL-18. Nlrp1, the first receptor identified with inflammasome-forming capacity, is highly expressed in both the skin and immune cells. Despite its prominent role in these tissues, the function of Nlrp1 in melanoma remains poorly characterized. In this study, we investigated the impact of Nlrp1 on melanoma patient survival and found that its expression is associated with improved prognosis and with a co-expression network enriched for pro-inflammatory genes. However, in murine models, neither Nlrp1 expression nor activation significantly affected melanoma development or progression. Similarly, pharmacological activation of Nlrp1 using Val-Boro-Pro (VbP) did not alter tumor growth or the local inflammatory profile in mice but directly influenced CD25+ cell generation and glucose uptake in in vitro models. Finally, we demonstrated that a melanoma risk score can be constructed based on genes specific to inflammasome and pyroptosis pathways. Collectively, our findings reveal species-specific differences in NLRP1 function between humans and mice and support the potential of inflammasome-related pathways as prognostic biomarkers and therapeutic targets in human cancers.

immunology↗

bioRxiv2024

Th17 cells require the DNA repair sensor XPC to control oxidative DNA damage

Th17 cells are critical for mucosal immunity, producing IL-17A, IL-17F, and IL-22, but dysregulated Th17 responses are implicated in autoimmune diseases. Despite their susceptibility to oxidative stress in certain conditions, Th17 cells exhibit reduced oxidative DNA damage and cell death compared to other T helper subsets. However, the mechanisms that protect Th17 cells from oxidative stress are poorly understood. Here, we identify Xeroderma Pigmentosum Complementation Group C (XPC) as a key regulator of DNA repair and genomic stability in Th17 cells. In XPC-deficient mice, we demonstrate that the absence of XPC impairs Th17 differentiation, as evidenced by reduced expression of key differentiation markers, including Rorc and Il17a, along with decreased IL-17A production. This deficiency leads to increased oxidative stress, DNA damage, and a metabolic shift from glycolysis to oxidative phosphorylation. Moreover, the transcription factor BATF directly regulates XPC expression, linking the BATF-XPC axis to the maintenance of Th17 cell function. Importantly, we find that restoring antioxidant capacity with N-Acetylcysteine (NAC) rescues IL-17A production and reduces DNA damage in XPC-deficient Th17 cells. Mechanistically, we find that XPC interacts with OGG1, a DNA glycosylase involved in the repair of oxidative DNA damage, highlighting XPCs role in maintaining genomic integrity during Th17 cell differentiation. Our findings reveal a previously unrecognized role for XPC in protecting Th17 cells from oxidative stress, ensuring their proper differentiation and function, with potential implications for targeting DNA repair pathways in autoimmune and inflammatory diseases.

immunology↗