Biology subjects

Quinton, L. J.

Publications and source records attributed to Quinton, L. J..

5 recordsLinked to original sources

bioRxiv2026

Non-canonical Oncostatin M Signaling Provides Protection during Respiratory Viral and Bacterial infections

Pneumonia remains a major global health burden, highlighting the need for host-directed therapies to complement antimicrobial treatment. Here, we identify Oncostatin M (OSM) as a critical regulator of pulmonary host responses during influenza and bacterial pneumonia. Loss of OSM shifted lung macrophages toward a pro-inflammatory phenotype during influenza infection and exacerbated lung injury during bacterial pneumonia, demonstrating an essential role for OSM in limiting immunopathology. Unexpectedly, OSM induced Signal Transducer and Activator of Transcription 3 (STAT3) activation in the absence of the canonical OSM receptor subunit OSMr{beta}, revealing previously unrecognized non-canonical OSM signaling in the mouse lungs. Consistent with this finding, loss of OSMr{beta} did not phenocopy the severe disease observed with loss of OSM. Together, these findings identify OSM as a key regulator of pulmonary immunity and reveal unexpected complexity in OSM signaling during pneumonia.

immunology↗

bioRxiv2024

Neutrophil transcriptome diverges into two discrete trajectories in a murine model of severe Streptococcus pneumoniae pneumonia

Neutrophils were once considered a homogenous population of transcriptionally static, pathogen-killing cells, however, recent models have demonstrated neutrophil functional and transcriptional plasticity. We performed transcriptomic analyses in a murine model of pneumococcal pneumonia to investigate neutrophil plasticity and demonstrate that neutrophils are highly dynamic, leading to three distinct alveolar neutrophil populations - one immature (early bronchoalveolar lavage neutrophils [BALN]) and two mature (late BALN). Early BALNs produce high levels of inflammatory cytokine transcripts, maturing into late BALNs, including a pro-degranulation and phagocytosis population (late-degranulating BALN) or a population specializing in translation machinery and inflammatory cytokine production (late-cytokine producing BALN). Neutrophil metabolism is also regulated in a stepwise manner - tricarboxylic acid (TCA) cycle and respiratory electron transport chain (ETC) genes are downregulated as neutrophils migrate from the vasculature to the interstitium, lipid and carbohydrate metabolism genes are downregulated during migration from interstitium to the airspace. These transitions may be regulated by aspects of the integrated stress response (ISR), as key regulators including Eif2ak2 are upregulated in interstitial neutrophils. Overall, we demonstrate that pneumonic neutrophils are transcriptionally plastic, developing through two distinct transcriptional phenotypes in the airspace, and are metabolically and transcriptionally rewired with potential points of regulation occurring in the interstitial space.

immunology↗

bioRxiv2024

Lung CD4+ resident memory T cells use airway secretory cells to stimulate and regulate neutrophilic allergic airways disease.

Neutrophilic asthma is a vexing disease, but mechanistic and therapeutic advancement will require better models of allergy-induced airway neutrophilia. Here, we find that periodic ovalbumin (OVA) inhalation in sensitized mice elicits allergic airway inflammation and pathophysiology mimicking neutrophilic asthma. OVA-experienced murine lungs harbor diverse clusters of CD4+ resident memory TRM cells, including unconventional ROR{gamma}tnegative/low TH17 cells. Acute OVA challenge instigates IL-17A secretion from these TRM cells, driving CXCL5 production from Muc5achigh airway secretory cells, leading to destructive airway neutrophilia. The TRM- and epithelial-cell signals discovered herein are also observed in adult human asthmatic airways. Epithelial antigen presentation regulates this biology by skewing TRM cells towards TH2 and TH1 fates, so that the TH1-related IFN-{gamma} suppresses IL-17A-driven, CXCL5-mediated airway neutrophilia. Concordantly, in vivo IFN-{gamma} supplementation improves disease outcomes. Thus, using our model of neutrophilic asthma we identify lung epithelial-CD4+ TRM cell crosstalk as a key rheostat of allergic airway neutrophilia. HighlightsO_LIRecurrent OVA inhalation experience predisposes mice to allergic airways neutrophilia C_LIO_LINeutrophil-prone lungs harbor CD4+ TRM cells including ROR{gamma}tnegative/low TH17 cells C_LIO_LIMuc5achigh secretory cells instruct CD4+ TRM fates and neutrophilia via MHC-II and CXCL5, respectively C_LIO_LIProphylactic or therapeutic delivery of IFN-{gamma} curbs allergic airway neutrophilia C_LI

immunology↗

bioRxiv2023

Expression of a STING Gain-of-function Mutation in Endothelial Cells Initiates Lymphocytic Infiltration of the Lungs

Patients afflicted with STING gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in the initiation of ILD. To identify STING-expressing non-hematopoietic cell types relevant to ILD, we generated a conditional knock-in (CKI) model in which expression of the VM allele was directed to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted expression of the mutant allele resulted in the recruitment of immune cells to the lung and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of SAVI patients or patients afflicted with other ILD-related disorders. SummaryPatients with STING gain-of-function (GOF) mutations develop life-threatening lung autoinflammation. In this study, Gao et al. utilize a mouse model of conditional STING GOF to demonstrate a role for endothelial STING GOF in initiating immune cell recruitment into lung tissues of SAVI mice.

immunology↗

bioRxiv2020

IL-27 enhances the lymphocyte mediated innate resistance to primary hookworm infection in the lungs

Interleukin-27 (IL-27) is a heterodimeric cytokine of the IL-12 family, formed by non-covalent association of the promiscuous EBI3 subunit and selective p28 subunit. IL-27 is produced by mononuclear phagocytes and unfolds pleiotropic immune-modulatory functions through high affinity ligation to IL-27 receptor alpha (IL-27RA). While IL-27 is known to contribute to immunity and to end inflammation following numerous types of infections, its relevance for host defense against multicellular parasites is still poorly defined. Here, we investigated the role of IL-27 during infection with the soil-transmitted hookworm, Nippostrongylus brasiliensis, in its early intrapulmonary life cycle. IL-27(p28) was detectable in broncho-alveolar lavage fluids of C57BL/6J wild type mice on day 1 after subcutaneous N. brasiliensis inoculation. The expression of IL-27RA was most abundant on lung invading {gamma}{delta} T cells followed by CD8+ T cells, CD4+ T cells and NK cells. IL-27RA was weakly present on CD19+ B cells and absent on neutrophils, alveolar macrophages and eosinophils. Il27ra-/- mice showed increased parasite burden together with aggravated pulmonary hemorrhage and higher alveolar albumin leakage as a surrogate for disruption of the epithelial/vascular barrier. Conversely, recombinant mouse IL-27 injections of wild type mice reduced parasite burdens and lung injury. In multiplex screens, we identified higher airway accumulations of IL-6, TNF and MCP-3 (CCL7) in Il27ra-/- mice, while rmIL-27 treatment showed a reciprocal effect. Finally, {gamma}{delta} T cell infiltration of the airways required endogenous IL-27 expression. In summary, this report demonstrates protective functions of IL-27 to control the early larval stage of hookworm infection in the lungs.

immunology↗