Dynamic behavior and lineage plasticity of the pulmonary venous endothelium.

Repair of the pulmonary vascular bed and the origin of new vasculature remain underexplored despite the critical necessity to meet oxygen demands after injury. Given their critical role in angiogenesis in other settings, we investigated the role of venous endothelial cells in endothelial regeneration after adult lung injury. Here we identified Slc6a2 as a marker of pulmonary venous endothelial cells and generated a venous-specific, inducible Cre mouse line.

Disruption of immune responses by type 1 diabetes exacerbates SARS-CoV-2 mediated lung injury.

COVID-19 commonly presents as pneumonia, with those most severely affected progressing to respiratory failure. Patient responses to SARS-CoV-2 infection are varied, with comorbidities acting as major contributors to varied outcomes. Focusing on one such major comorbidity, we assessed whether pharmacological induction of type 1 diabetes mellitus (T1DM) would increase the severity of lung injury in a murine model of COVID-19 pneumonia utilizing wild-type mice infected with mouse-adapted SARS-CoV-2.

Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation.

Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury.

TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue.

Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are critical determinants of the outcome of severe lung injury. A more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium is necessary to facilitate therapeutic vascular repair. Here, we demonstrated that TGF-β signaling through TGF-βR2 (transforming growth factor-β receptor 2) is activated in pulmonary ECs upon influenza infection, and mice deficient in endothelial exhibited prolonged injury and diminished vascular repair.

[WITHDRAWN] Neuron-dependent tuft cell expansion initiates sinonasal allergic Type 2 inflammation.

The authors have withdrawn this manuscript owing to inaccuracies in the calculation of tuft cell numbers and errors in the selection of immunofluorescence images used to support our claims. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation.

Inflammation upon infectious lung injury is a double-edged sword: while tissue-infiltrating immune cells and cytokines are necessary to control infection, these same factors often aggravate injury. Full appreciation of both the sources and targets of inflammatory mediators is required to facilitate strategies to maintain antimicrobial effects while minimizing off-target epithelial and endothelial damage. Recognizing that the vasculature is centrally involved in tissue responses to injury and infection, we observed that pulmonary capillary endothelial cells (ECs) exhibit dramatic transcriptomic changes upon influenza injury punctuated by profound upregulation of .

ΔNp63 drives dysplastic alveolar remodeling and restricts epithelial plasticity upon severe lung injury.

The lung exhibits a robust, multifaceted regenerative response to severe injuries such as influenza infection, during which quiescent lung-resident epithelial progenitors participate in two distinct reparative pathways: functionally beneficial regeneration via alveolar type 2 (AT2) cell proliferation and differentiation, and dysplastic tissue remodeling via intrapulmonary airway-resident basal p63 progenitors. Here we show that the basal cell transcription factor ΔNp63 is required for intrapulmonary basal progenitors to participate in dysplastic alveolar remodeling following injury. We find that ΔNp63 restricts the plasticity of intrapulmonary basal progenitors by maintaining either active or repressive histone modifications at key differentiation gene loci.

Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair.

While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5 dysplastic regions after influenza injury.

Helminth-induced reprogramming of the stem cell compartment inhibits type 2 immunity.

Enteric helminths form intimate physical connections with the intestinal epithelium, yet their ability to directly alter epithelial stem cell fate has not been resolved. Here we demonstrate that infection of mice with the parasite Heligmosomoides polygyrus bakeri (Hpb) reprograms the intestinal epithelium into a fetal-like state marked by the emergence of Clusterin-expressing revival stem cells (revSCs). Organoid-based studies using parasite-derived excretory-secretory products reveal that Hpb-mediated revSC generation occurs independently of host-derived immune signals and inhibits type 2 cytokine-driven differentiation of secretory epithelial lineages that promote their expulsion.

An Epidemic Zika Virus Isolate Drives Enhanced T Follicular Helper Cell and B Cell-Mediated Immunity.

Zika virus (ZIKV) is a mosquito-borne pathogen that recently caused a series of increasingly severe outbreaks. We previously demonstrated that, compared with a pre-epidemic isolate (ZIKV), a Brazilian ZIKV isolate (ZIKV) possesses a novel capacity to suppress host immunity, resulting in delayed viral clearance. However, whether ZIKV modulates CD4 T cell responses remains unknown.

NK cell recruitment limits tissue damage during an enteric helminth infection.

Parasitic helminths cause significant damage as they migrate through host tissues to complete their life cycle. While chronic helminth infections are characterized by a well-described Type 2 immune response, the early, tissue-invasive stages are not well understood. Here we investigate the immune pathways activated during the early stages of Heligmosomoides polygyrus bakeri (Hpb), a natural parasitic roundworm of mice.

CD109 Restrains Activation of Cutaneous IL-17-Producing γδ T Cells by Commensal Microbiota.

Interleukin-17-producing γδ T (γδ17) cells play a central role in protective and pathogenic immune responses. However, the tissue-specific mechanisms that control the activation of these innate lymphocytes are not known. Here, we demonstrate that CD109, a glycosylphosphatidylinositol (GPI)-anchored protein highly expressed by keratinocytes, is an important regulator of skin homeostasis and γδ17 cell activation.