Coulie, P. G. | Search bioRxiv

bioRxiv2025

The phosphate exporter XPR1 regulates a gasdermin D-independent mature IL-1β secretion pathway in LPS-stimulated human monocytic cells

The inflammatory cytokine interleukin (IL)-1{beta} is a leaderless protein that is not secreted via the classical endoplasmic reticulum-Golgi pathway but instead is secreted during pyroptosis, a form of caspase-dependent inflammatory cell death mediated by gasdermin D (GSDMD) cleavage and pore formation at the plasma membrane. However, human monocytes can secrete IL-1{beta} in the absence of cell death, and the contribution of GSDMD in this secretory pathway is not established. Here, we identify two mechanisms of mature IL-1{beta} secretion by living human monocytic cells: a rapid, GSDMD-dependent pathway and a slower, GSDMD-independent pathway. Using a CRISPR-Cas9 loss-of-function screen, we identified XPR1 (Xenotropic and Polytropic retrovirus Receptor 1) as a key regulator of the GSDMD-independent pathway. XPR1 is the only phosphate exporter identified in metazoans and has no previously described function in cytokine secretion. XPR1 invalidation in GSDMD-/- monocytic cells impaired IL-1{beta} secretion. We further show that this regulatory function requires cell-surface expression of XPR1 and is linked to its phosphate export activity. Our results reveal a previously undescribed mechanism of IL-1{beta} secretion by living human monocytic cells, independent of GSDMD and unexpectedly linked to phosphate homeostasis. Deciphering this pathway could lead to new therapeutic modalities for IL-1{beta}-driven inflammatory diseases.

immunology↗

bioRxiv2025

CD8 T lymphocytes infiltrate the kidneys and correlate with disease progression in B6.NZMSle1/Sle2/Sle3 lupus mice

BackgroundLupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) characterized by immune-mediated renal damage. While intrarenal CD8+ T cell infiltration has been linked to disease activity in patients, their pathogenic contribution remains unclear, partly due to the lack of mechanistic insight from murine models. MethodsWe investigated renal CD8+ T cell infiltration in female B6.NZMSle1/Sle2/Sle3 lupus-prone mice across different ages, comparing them to C57BL/6 controls. Histopathology was assessed using human-derived NIH Activity and Chronicity Indices, complemented by fibrosis quantification, immunohistochemistry, and digital image analysis. Kidney T cell subsets were evaluated by flow cytometry, and transcriptomic profiling was performed using microarrays. ResultsLupus-prone mice developed progressive kidney injury resembling human LN, with increasing NIH activity scores, collagen deposition, however with interindividual heterogeneity. CD8+ T cell infiltrates were significantly elevated in lupus kidneys as early as 3 months, rising with age and correlating with histological activity. CD8+ T cells localized to periglomerular and peritubular regions but did not predominate over CD4+ T cells, as confirmed by flow cytometry. Transcriptomic analyses revealed age-dependent upregulation of interferon (IFN)-stimulated genes, B cell-associated transcripts, and extracellular matrix remodeling pathways, while T cell- related signatures were more variable. ConclusionsB6.NZMSle1/Sle2/Sle3 mice recapitulate several histopathological and molecular features of human LN, including progressive fibrosis and intrarenal CD8+ T cell infiltration that correlate with disease severity. However, the absence of CD8+ predominance suggests limitations of this model for dissecting CD8+ T cell-specific contributions to LN pathogenesis. Yet, these findings underscore the need to identify renal antigens driving CD8+ T cell responses in human LN.

immunology↗