Biology subjects

Budinger, G. R. S.

Publications and source records attributed to Budinger, G. R. S..

10 recordsLinked to original sources

bioRxiv2026

Interstitial macrophages drive chronic lung allograft dysfunction

Despite immunosuppressive regimens targeting adaptive immunity, chronic lung allograft dysfunction (CLAD) remains the major obstacle to durable lung allograft survival. Here, we identify colony-stimulating factor 1 receptor (CSF1R)-expressing interstitial macrophages as critical orchestrators of CLAD. Using lung tissue from patients with CLAD and a mouse model of mismatched lung transplantation, we show that both donor-derived tissue-resident and recipient- monocyte-derived interstitial macrophages spatially co-localize within peribronchial immune aggregates in patients with CLAD. These interstitial macrophages express distinct cytokine programs that include those implicated in the recruitment of T and B cells. Pharmacological inhibition of CSF1R after lung transplantation in mice reduced interstitial macrophage abundance and attenuated CLAD pathology. Our findings identify donor- and recipient-derived interstitial macrophages as upstream regulators of CLAD and suggest CSF1R as a therapeutic target for its prevention and treatment.

immunology↗

bioRxiv2026

VEGFA-Positive Macrophages Regulate Aqueous Humor Outflow in Aged Mice and Humans

Elevated intraocular pressure (IOP) and aging are major risk factors for primary open-angle glaucoma (POAG), but how aging affects IOP regulation remains poorly understood. IOP remains within a narrow range despite age-associated changes predicted to increase aqueous humor outflow (AHO) resistance at the interface between the trabecular meshwork and Schlemm's canal (SC), suggesting compensatory mechanisms preserve AHO homeostasis during aging. Single-cell RNA sequencing of mouse ocular angle tissues revealed immunomodulatory transcriptional reprogramming of SC endothelial cells in older mice, while mouse and human imaging showed reduced SC size and increased peri-SC macrophage accumulation with aging. Ligand-receptor analysis predicted enhanced macrophage-to-SC VEGFA-VEGFR signaling in aged and Tie2-haploinsufficient mice, an independent model of vascular stress and glaucoma risk. Deletion of Vegfa in CX3CR1+ macrophages increased IOP and reduced AHO facility in 9-month-old mice, demonstrating that macrophage-derived VEGFA supports AHO homeostasis. Tie2 haploinsufficiency recapitulated key age-associated SC niche changes, including peri-SC macrophage accumulation, whereas gene therapy boosting TIE2 activity protected wild-type mice against age-related changes. Together, these findings identify peri-SC macrophage-derived VEGFA as a compensatory mechanism maintaining AHO homeostasis during aging and vascular stress and support TIE2 activation as a therapeutic strategy to preserve SC function and IOP regulation.

physiology↗

bioRxiv2026

Identity, ontogeny, and age-related changes in splenic white pulp macrophages in mouse and human spleen

The spleen contains diverse macrophage subsets that remove aged erythrocytes, prevent the dissemination of circulating pathogens, and shape the adaptive immune response1-3. The mouse spleen hosts red pulp macrophages (RPM), marginal zone macrophages (MZM), marginal zone metallophilic macrophages (MMM), and tingible body macrophages (TBM). However, their transcriptomic identity, ontogeny, and dynamics during aging are unknown. Furthermore, it is not known whether homologous populations of macrophages exist in the human spleen. We find that in mice, MZM and MMM are tissue-resident macrophages that maintain their population via local proliferation, while TBM are slowly replaced by circulating monocytes. Lineage tracing shows that MMM maintain the MZM pool, and that after MMM depletion, circulating monocytes restore MMM. We show that a decrease in MMM abundance in aging precedes changes in other cellular populations and splenic niches. In human spleen, we identify TBM and perifollicular zone macrophages (PFZM) as a single macrophage population homologous to MMM and MZM in mice. We show that in both mouse and human TBM become more abundant during aging. Our results suggest age-related changes in the splenic microenvironment drive changes in tissue-resident splenic macrophage populations with potential importance for the loss of immunologic function in older individuals.

immunology↗

bioRxiv2023

Prolonged exposure to lung-derived cytokines is associated with inflammatory activation of microglia in patients with COVID-19

Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia1-4. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans5. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF-[a] and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-196, was associated with lower levels of CXCL10, CCL8, and CCL2--molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells7. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19.

immunology↗

bioRxiv2023

Myeloid Zfhx3 Deficiency Protects Against Hypercapnia-induced Suppression of Host Defense Against Influenza A Virus

Hypercapnia, elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that elevated CO2 increases the mortality of bacterial and viral pneumonia in mice. Here, we show that normoxic hypercapnia downregulates innate immune and antiviral gene programs in alveolar macrophages (AMOs). We also show that zinc finger homeobox 3 (Zfhx3), mammalian ortholog of zfh2, which mediates hypercapnic immune suppression in Drosophila, is expressed in mouse and human MOs. Deletion of Zfhx3 in the myeloid lineage blocked the suppressive effect of hypercapnia on immune gene expression in AMOs and decreased viral replication, inflammatory lung injury and mortality in hypercapnic mice infected with influenza A virus. Our results establish Zfhx3 as the first known mammalian mediator of CO2 effects on immune gene expression and lay the basis for future studies to identify therapeutic targets to interrupt hypercapnic immunosuppression in patients with advanced lung diseases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/530480v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@f6f907org.highwire.dtl.DTLVardef@577795org.highwire.dtl.DTLVardef@6c0068org.highwire.dtl.DTLVardef@8ebb72_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Hypercapnia limits β-catenin mediated alveolar type 2 cell progenitor function by altering Wnt production from adjacent fibroblasts

Persistent symptoms and radiographic abnormalities suggestive of failed lung repair are among the most common symptoms in patients with COVID-19 after hospital discharge. In mechanically ventilated patients with ARDS secondary to SARS-CoV-2 pneumonia, low tidal volumes to reduce ventilator-induced lung injury necessarily elevate blood CO2 levels, often leading to hypercapnia. The role of hypercapnia on lung repair after injury is not completely understood. Here, we show that hypercapnia limits {beta}-catenin signaling in alveolar type 2 (AT2) cells, leading to reduced proliferative capacity. Hypercapnia alters expression of major Wnts in PDGFRa+-fibroblasts from those maintaining AT2 progenitor activity and towards those that antagonize {beta}-catenin signaling and limit progenitor function. Activation of {beta}-catenin signaling in AT2 cells, rescues the inhibition AT2 proliferation induced by hypercapnia. Inhibition of AT2 proliferation in hypercapnic patients may contribute to impaired lung repair after injury, preventing sealing of the epithelial barrier, increasing lung flooding, ventilator dependency and mortality.

cell biology↗

bioRxiv2021

Pharmacological inhibition of PAI-1 alleviates cardiopulmonary pathologies induced by exposure to air pollutants PM2.5

OBJECTIVEExposure to air pollutants leads to the development of pulmonary and cardiovascular diseases, and thus air pollution is one of the major global threats to human health. Air pollutant particulate matter 2.5 (PM2.5)-induced cellular dysfunction impairs tissue homeostasis and causes vascular and cardiopulmonary damage. To test a hypothesis that elevated plasminogen activator inhibitor-1 (PAI-1) levels play a pivotal role in air pollutant-induced cardiopulmonary pathologies, we examined the efficacy of a drug-like novel inhibitor of PAI-1, TM5614, in treating PM2.5-induced vascular and cardiopulmonary pathologies. APPROACH AND RESULTSResults from biochemical, histological, and immunohistochemical studies revealed that PM2.5 increases the circulating levels of PAI-1 and thrombin and that TM5614 treatment completely abrogates these effects in plasma. PM2.5 significantly augments levels of pro-inflammatory cytokine IL-6 in bronchoalveolar lavage fluid, and this also can be reversed by TM5614, indicating its efficacy in amelioration of PM2.5-induced increases in inflammatory and pro-thrombotic factors. TM5614 reduces PM2.5-induced increased levels of inflammatory markers Mac3 and pSTAT3, adhesion molecule VCAM1, and apoptotic marker cleaved caspase 3. Longer exposure to PM2.5 induces pulmonary and cardiac thrombosis, but TM5614 significantly ameliorates PM2.5-induced vascular thrombosis. TM5614 also reduces PM2.5-induced increased blood pressure and heart weight. In vitro cell culture studies revealed that PM2.5 induces the levels of PAI-1, type I collagen, fibronectin, and SREBP-1/2, a transcription factor that mediates profibrogenic signaling, in cardiac fibroblasts. TM5614 abrogated that stimulation, indicating that it may block PM2.5-induced PAI-1 and profibrogenic signaling through suppression of SREBP-1. Furthermore, TM5614 blocked PM2.5-mediated suppression of Nrf2, a major antioxidant regulator in cardiac fibroblasts. CONCLUSIONSPharmacological inhibition of PAI-1 with TM5614 is a promising therapeutic approach to control air pollutant PM2.5-induced cardiopulmonary and vascular pathologies. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

pharmacology and toxicology↗

bioRxiv2020

Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A 1 Infection via Akt1

Hypercapnia, elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that it increases the mortality of bacterial pneumonia in mice. Here, we show that normoxic hypercapnia increases viral replication, lung injury and mortality in mice infected with influenza A virus (IAV). Elevated CO2 increased IAV replication and inhibited antiviral gene and protein expression in macrophages in vivo and in vitro. Hypercapnia potentiated IAV-induced activation of Akt, while specific pharmacologic inhibition or shRNA knockdown of Akt1 in alveolar macrophages blocked hypercapnias effects on IAV growth and the macrophage antiviral response. Our findings suggest that targeting Akt1 or downstream pathways through which elevated CO2 signals could enhance macrophage antiviral host defense and improve clinical outcomes in hypercapnic patients with advanced lung disease.

immunology↗

bioRxiv2019

Proteostasis and Energetics as Proteome Hallmarks of Aging and Influenza Challenge in Pulmonary Disease

Aging is associated with an increased risk for the development of many diseases. This is exemplified by the increased incidence of lung injury, muscle dysfunction and cognitive impairment in the elderly following influenza infection. Because the infectious cycle of flu is dependent upon the properties of the host, we examined the proteome of alveolar macrophages (AM) and type 2 cells (AT2) obtained from young (3 months) and old (18 months) naive mice and mice exposed to influenza A. Our proteomics data show that there is a maladaptive collapse of the proteostasis network (PN) and changes in mitochondrial pathways in the aged naive AM and AT2 proteomes. The mitochondrial imbalance and proteostatic collapse seen in aged cells places an excessive folding burden on these cells, which is further exacerbated following exposure to influenza A. Specifically, we see an imbalance in Hsp70 co-chaperones involved in protein folding and Hsp90 co-chaperones important for stress signaling pathways that are essential for cellular protection during aging. The acute challenge of influenza A infection of young and aged AM and AT2 cells reveals that age-associated changes in the chaperome affect the ability of these cells to properly manage the infection and post-infection biology, contributing to cytotoxicity. We posit that proteomic profiling of individual cell type specific responses provides a high impact approach to pinpoint fundamental molecular relationships that may contribute to the susceptibility to aging and environmental stress, providing a platform to identify new targets for therapeutic intervention to improve resiliency in the elderly.

cell biology↗

bioRxiv2019

Aging is associated with a systemic length-driven transcriptome imbalance

Aging manifests itself through a decline in organismal homeostasis and a multitude of cellular and physiological functions1. Efforts to identify a common basis for vertebrate aging face many challenges; for example, while there have been documented changes in the expression of many hundreds of mRNAs, the results across tissues and species have been inconsistent2. We therefore analyzed age-resolved transcriptomic data from 17 mouse organs and 51 human organs using unsupervised machine learning3-5 to identify the architectural and regulatory characteristics most informative on the differential expression of genes with age. We report a hitherto unknown phenomenon, a systemic age-dependent length-driven transcriptome imbalance that for older organisms disrupts the homeostatic balance between short and long transcript molecules for mice, rats, killifishes, and humans. We also demonstrate that in a mouse model of healthy aging, length-driven transcriptome imbalance correlates with changes in expression of splicing factor proline and glutamine rich (Sfpq), which regulates transcriptional elongation according to gene length6. Furthermore, we demonstrate that length-driven transcriptome imbalance can be triggered by environmental hazards and pathogens. Our findings reinforce the picture of aging as a systemic homeostasis breakdown and suggest a promising explanation for why diverse insults affect multiple age-dependent phenotypes in a similar manner.

systems biology↗