Biology subjects

Santiago-Carvalho, I.

Publications and source records attributed to Santiago-Carvalho, I..

5 recordsLinked to original sources

bioRxiv2025

Escherichia coli-induced gut IL-33 release inhibits lung type 2 allergic responses

BackgroundThe incidence of lung allergies is reduced in countries with higher prevalence of infection and environmental exposure to microbes. However, enteric bacterial infections do not always correlate with lower incidence of allergic disorders and how lung immunity to allergens can be regulated by gut exposure to pathogens and their toxins is not fully understood. ObjectiveWe used mouse models of enterotoxigenic Escherichia coli (ETEC) infection and lung allergy to examine how gut exposure to bacteria, or their related toxins, affects allergic lung inflammation. MethodsNaive C57BL/6 mice were infected with enterotoxigenic Escherichia coli (ETEC) or orally treated with the ETEC LT toxin, to mimic enteric bacterial infections. After two weeks, these mice were treated intranasally with Ovalbumin (OVA) and Papain or IL-33, followed by challenge with OVA, to induce allergic lung inflammation that was assessed using multiple readouts. ResultsGut exposure to ETEC significantly inhibited allergic lung inflammation in a LT-dependent manner, as demonstrated by reduced tissue inflammation, less accumulation of type 2 cytokines, and reduced lung numbers of type 2 immune cells such as type 2 innate lymphoid cells (ILC2) and eosinophils. The anti-allergic capacity of LT was associated with reduced ability of lung ILC2s to recognize IL-33. Counterintuitively, deletion of either IL-33 or ILC2s significantly reverted the LT protective effect, suggesting the LT-mediated protection may occur through gut release and local sensing of IL-33. ConclusionsExposure to ETEC protects hosts against allergic lung inflammation through a negative feedback loop regulated by gut IL-33 release and sensing, suggesting a possible new immunological mechanism for reduced lung allergy incidence observed in areas with enteric bacterial infections. Key Messages- Enteric exposure to enterotoxigenic E. coli (ETEC) bacteria or its toxin LT significantly protects hosts against lung type 2 allergic inflammation. - ETEC and LT downregulate the capacity of lung ILC2s to respond to allergen-induced IL-33. - Deletion of IL-33 or ILC2s significantly impairs the protective effect of ETEC and LT, suggesting the presence of a negative feedback loop driven by toxin-induced gut IL-33 release.

immunology↗

bioRxiv2025

CD39 REGULATES P2RX7-MEDIATED LUNG NECROTIC LESIONS IN SEVERE EXPERIMENTAL TUBERCULOSIS

Tuberculosis induces diverse lesions, such as necrotic pneumonia, contributing to disease progression and transmission. Despite advances in understanding the role of ATP-gated P2RX7 ion channels in developing severe forms of tuberculosis, the regulation of this important signaling pathway remains unclear. Herein, we show that the ectonucleotidase CD39 plays an essential regulatory role in TB progression by preventing lung tissue damage, bacterial dissemination, and excessive inflammatory responses. Mechanistically, through its enzymatic activity on the cellular surface, CD39 protects infected macrophages from undergoing necrotic death mediated by P2RX7 activation. We proposed that by protecting macrophages from P2RX7-mediated cell death and bacterial dissemination, CD39 prevents the development of necrotic lesions. Altogether, these findings uncover a significant role for CD39 as an essential component of the molecular regulation underlying the development of severe tuberculosis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/656614v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1dc7320org.highwire.dtl.DTLVardef@a4202org.highwire.dtl.DTLVardef@173bb62org.highwire.dtl.DTLVardef@1132f0f_HPS_FORMAT_FIGEXP M_FIG C_FIG BriefIn tuberculosis, necrotic granuloma-like structures release extracellular ATP (eATP), which triggers P2RX7-mediated immune cell death. CD39 degrades eATP, preventing P2RX7 activation and promoting macrophage survival, thereby limiting inflammation, tissue damage, and bacterial dissemination.

immunology↗

bioRxiv2025

Sensing of extracellular ATP via P2RX7 drives lung tumor growth through regulatory T cell suppressive function

Lung cancer is the leading cause of cancer-related deaths worldwide and, despite treatment advances, immune suppression remains an obstacle to effective therapy. Effector CD4+ T cells (CD4+ Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and perform suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Here, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. Using a murine lung cancer model induced by Lewis lung carcinoma cells, we demonstrate that P2RX7 enhances the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4+ Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibit reduced tumor growth, confirming a cell-intrinsic role of P2RX7 in Tregs. Suppression assays revealed that tumor-infiltrating WT Tregs have greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that WT Tregs express higher levels of the immunosuppressive surface molecule CTLA-4 when compared to P2RX7-KO Tregs. In summary, we show that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer, and targeting of P2RX7 may constitute a novel strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

immunology↗

bioRxiv2023

Pannexin-1 channels promote CD8+ T cell effector and memory responses through distinct intracellular pathways

Sensing of extracellular ATP (eATP) controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Whether Panx1 controls CD8+ T cell immune responses in vivo, however, has not been previously addressed. Here, we report that T cell-specific Panx1 is needed for CD8+ T cell responses to viral infections and cancer. We found that CD8-specific Panx1 promotes both effector and memory CD8+ T cell responses. Panx1 favors initial effector CD8+ T cell activation through extracellular ATP (eATP) export and subsequent P2RX4 activation, which helps promote full effector differentiation through extracellular lactate accumulation and its subsequent recycling. In contrast, Panx1 promotes memory CD8+ T cell survival primarily through ATP export and subsequent P2RX7 engagement, leading to improved mitochondrial metabolism. In summary, Panx1-mediated eATP export regulates effector and memory CD8+ T cells through distinct purinergic receptors and different metabolic and signaling pathways.

immunology↗

bioRxiv2022

T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections

CD4+ T cells are key components of the immune response during lung infections and can mediate protection against tuberculosis (TB) or influenza. However, CD4+ T cells can also promote lung pathology during these infections, making it unclear how these cells control such discrepant effects. Using mouse models of hypervirulent TB and influenza, we observed that exaggerated accumulation of parenchymal CD4+ T cells promotes lung damage. Low numbers of lung CD4+ T cells, in contrast, are sufficient to protect against hypervirulent TB. In both situations, lung CD4+ T cell accumulation is mediated by CD4+ T cell-specific expression of the extracellular ATP (eATP) receptor P2RX7. P2RX7 upregulation in lung CD4+ T cells promotes expression of the chemokine receptor CXCR3 and favors in situ proliferation. Our findings suggest that direct sensing of lung eATP by CD4+ T cells is critical to induce tissue CD4+ T cell accumulation and pathology during lung infections. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/508603v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@a4cdaborg.highwire.dtl.DTLVardef@1ba95e1org.highwire.dtl.DTLVardef@c60984org.highwire.dtl.DTLVardef@19ac0af_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗