Biology subjects

Behrens, E. M.

Publications and source records attributed to Behrens, E. M..

7 recordsLinked to original sources

bioRxiv2026

T cell dysregulation and remodeling in pediatric obesity and weight loss

Obesity is a chronic inflammatory disease associated with immune dysregulation. However, alterations in adaptive immune function remain unclear, particularly in the setting of childhood obesity and weight loss. We defined peripheral T cell dysregulation in a cross-sectional cohort of pediatric participants across weight categories and in a longitudinal cohort of adolescents with severe obesity undergoing bariatric surgery. We found increased expression of activation markers (including PD-1 and CD69) in non-naive CD8+ T cells whereas non-naive CD4+ T cells were skewed towards Tfh, Th17, and mixed Th2/Th17 populations. Consistent with a hyperactive state, T cells had enhanced capacity for inflammatory cytokine production (including IFN-{gamma} and TNF-), along with enrichment of gene sets associated with cytokine signaling, cell proliferation, and cell death. Notably, these phenotypic, functional, and transcriptional alterations were not fully resolved after bariatric surgery, despite clinically meaningful weight loss. Together, these findings demonstrate that pediatric obesity leads to dysregulation of adaptive immune function with incomplete normalization after weight loss. SUMMARYThe impact of pediatric obesity on immune cell function is not well understood. This study demonstrates that both CD4+ and CD8+ T cells are dysregulated in children living with obesity and further identifies that this dysregulated state persists following clinically significant weight loss.

immunology↗

bioRxiv2026

Damaged glomeruli in proliferative pediatric lupus nephritis exhibit a C5a-C5aR1 induced fibrotic transcriptional program

Lupus nephritis (LN) is a leading cause of morbidity in pediatric systemic lupus erythematosus (pSLE) due to suboptimal kidney remission rates and the sequelae of prolonged intensive immunosuppressive therapy. LN is patchy, with some glomeruli severely damaged while others remain histologically unaffected in the same kidney. Using spatial transcriptomic technology, we interrogated microanatomic transcriptional differences between histologically damaged and unaffected glomeruli in pSLE LN to understand local drivers of renal injury. Despite SLE being a disease of Type I interferon (IFN), IFN gene response does not associate with local glomerular damage. Rather, damage associates with a transcriptional module of higher expression of myeloid cell markers, C5AR1 (encoding the receptor for complement component 5a [C5a]), early complement components, and fibrosis genes. Bulk RNA-sequencing of C5a stimulated human monocyte-derived-macrophages revealed upregulation of tissue-remodeling and fibrosis-related pathways reversible by the C5aR1 inhibiting drug avacopan. These same C5a-inducible fibrosis genes were significantly upregulated in histologically damaged versus unaffected LN glomeruli providing a mechanistic link between C5a-C5aR1 signaling and early fibrosis in proliferative lupus nephritis. Our data provide insight into an understudied connection between complement activation and fibrosis relevant in SLE and likely other inflammatory diseases of complement activation.

immunology↗

bioRxiv2024

Akt2 deficiency impairs Th17 differentiation, augments Th2 differentiation, and alters the peripheral response to immunization

Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using mice with germline deletions of either Akt1 or Akt2, we found that both isoforms are important for Th17 differentiation, although Akt2 loss had a greater impact than loss of Akt1. In contrast to defective IL-17 production, Akt2-/- T cells exhibited enhanced IL-4 production in vitro under Th2 polarizing conditions. In vivo, Akt2-/- mice displayed significantly diminished IL-17A and GM-CSF production following immunization with myelin oligodendrocyte glycoprotein (MOG). This dampened response was associated with further alterations in Th cell differentiation including decreased IFN{gamma} production but preserved IL-4 production, and preferential expansion of regulatory T cells compared to non-regulatory CD4 T cells. Taken together, we identify Akt2 as an important signaling molecule in regulating peripheral CD4 T cell responses.

immunology↗

bioRxiv2023

Transcription Factor NRF2 is Activated by Erythrophagocytosis of Oxidized Red Blood Cell Products and Suppresses the IL-12-IFNg-IL-10 Axis in a Murine Model of Hyperinflammatory Disease

Hyperinflammatory diseases including macrophage activation syndrome (MAS) and hemophagocytic lymphohistocytosis (HLH) are characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. However, the mechanisms by which erythrophagocytosis mediates iron metabolism and regulates the hyperactive immune response remain unclear. The transcription factor NRF2 is an important sensor for inflammatory and redox distress. The targets of NRF2 are antioxidant response elements responsible for transcription of genes related to restoration of redox homeostasis within the cell. Here we demonstrate that mice with CpG-induced MAS have evidence of systemic oxidative and nitrosative distress - including increased serum nitric oxide and elevated systemic lipid peroxidation. In this model, NRF2 knockout mice develop significantly worse organomegaly, hypercytokinemia, and reticulocytosis. NRF2 knockout mice have unexpected exacerbation in the cytokines that are central to hyperinflammatory physiology - namely IL-12, IFN gamma (IFNg), and IL-10. In vitro we demonstrate that oxidized red blood cell products and heme itself suppress IL-12 protein production and transcription from bone marrow derived dendritic cells in a NRF2-dependent manner. Together our studies demonstrate that erythrophagocytosis of oxidized red blood cell products suppresses the Il-12-IFNg-IL-10 axis which drives hyperinflammation in murine hyperinflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/571271v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1a2330corg.highwire.dtl.DTLVardef@1c59944org.highwire.dtl.DTLVardef@1d151b5org.highwire.dtl.DTLVardef@14b4301_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender

immunology↗

bioRxiv2023

Biliatresone treatment of pregnant mice causes changes in bile metabolism and liver inflammation in their offspring

Background & AimsBiliary atresia is a neonatal disease characterized by bile duct and liver damage, fibrosis, inflammation and abnormal bile metabolism. It appears to result from a prenatal exposure that spares the mother and affects the fetus. Our aim was to define the phenotype in neonatal mice after maternal exposure to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock. MethodsPregnant mice were treated orally with low-doses of biliatresone. Histological changes, bile acid profiles and immune profiles were analyzed in postnatal day 5 and 21 pups born to treated mothers. ResultsThe pups of mothers treated with this dose of biliatresone had no evidence of significant liver or ductular injury or fibrosis at postnatal day 5 or 21 and they grew normally. However, serum levels of glycocholic acid were elevated at postnatal day 5, suggesting altered bile metabolism, and bile metabolism became increasingly abnormal through postnatal day 21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at postnatal day 21. ConclusionPrenatal exposure to low doses of an environmental toxin can cause liver inflammation and aberrant bile metabolism even in the absence of histological changes. Lay summaryPrenatal exposure to low doses of an environmental toxin can cause changes in bile metabolism in neonatal mice.

pharmacology and toxicology↗

bioRxiv2019

Interferons drive development of novel interleukin-15-responsive macrophages in the uterus

Disruption in homeostasis of interleukin-15 (IL-15) is linked to poor maternal and fetal outcomes during pregnancy. The only cells described to respond to IL-15 at the early maternal-fetal interface have been natural killer (NK) cells. We now show a novel population of macrophages, evident in several organs but enriched in the uterus of mice and humans, expressing the {beta} chain of the IL-15 receptor complex (CD122) and responding to IL-15. CD122+ macrophages (CD122+Macs) are morphologic, phenotypic, and transcriptomic macrophages that can derive from bone marrow monocytes. CD122+Macs develop in the uterus and placenta with kinetics that mirror interferon (IFN) activity at the maternal-fetal interface. Macrophage colony-stimulating factor (M-CSF) permits macrophages to express CD122, and IFNs are sufficient to drive expression of CD122 on macrophages. Neither Type-I nor Type-II IFNs are required to generate CD122+Macs, however. In response to IL-15, CD122+Macs activate the ERK signaling cascade and enhance production of proinflammatory cytokines after stimulation with the Toll-like receptor 9 agonist CpG. Finally, we provide evidence of human cells that phenocopy murine CD122+Macs in secretory phase endometrium during the implantation window and in first-trimester uterine decidua. Our data support a model wherein IFNs local to the maternal-fetal interface direct novel IL-15-responsive macrophages with the potential to mediate IL-15 signals critical for optimal outcomes of pregnancy. The microarray data presented in this article have been submitted to the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE132353.

immunology↗

bioRxiv2019

PIKfyve deficiency in myeloid cells impairs lysosomal homeostasis in macrophages and promotes systemic inflammation in mice

Macrophages are professional phagocytes that are essential for host defense and tissue homeostasis. Proper membrane trafficking and degradative functions of the endolysosomal system is known to be critical for the function of these cells. We have found that PIKfyve, the kinase that synthesizes the endosomal phosphoinositide PI(3,5)P2, is an essential regulator of lysosomal biogenesis and degradative functions in macrophages. Genetically engineered mice lacking PIKfyve in their myeloid cells (PIKfyvefl/fl LysM-Cre) develop diffuse tissue infiltration of foamy macrophages, hepatosplenomegaly, and systemic inflammation. PIKfyve loss in macrophages causes enlarged endolysosomal compartments and impairs the lysosomal degradative function. Moreover, PIKfyve deficiency increases the cellular levels of lysosomal proteins. Although PIKfyve deficiency reduced the activation of mTORC1 pathway and was associated with increased cleavage of TFEB proteins, this does not translate into transcriptional activation of lysosomal genes, suggesting that PIKfyve modulates the abundance of lysosomal proteins by affecting the degradation of these proteins. Taken together, our study shows that PIKfyve modulation of lysosomal degradative activity and protein expression is essential to maintain lysosomal homeostasis in macrophages.

cell biology↗