Severe burns induce a chronic hypermetabolic state that persists well past wound closure, indicating that additional internal mechanisms must be involved. Adipose tissue is suggested to be a central regulator in perpetuating hypermetabolism, although this has not been directly tested. Here, we show that thermogenic adipose tissues are activated in parallel to increases in hypermetabolism independent of cold stress. Using an adipose tissue transplantation model, we discover that burn-derived subcutaneous white adipose tissue alone is sufficient to invoke a hypermetabolic response in a healthy recipient mouse. Concomitantly, transplantation of healthy adipose tissue alleviates metabolic dysfunction in a burn recipient. We further show that the nicotinic acetylcholine receptor signaling pathway may mediate an immune-adipose crosstalk to regulate adipose tissue remodeling post-injury. Targeting this pathway could lead to innovative therapeutic interventions to counteract hypermetabolic pathologies.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

The increased prevalence of obesity and metabolic diseases has heightened interest in adipose tissue biology and its potential as a therapeutic target. To better understand cellular heterogeneity and complexity of white adipose tissue (WAT), we employed cytometry by time-of-flight (CyTOF) to characterize immune and stromal cells in visceral and subcutaneous WAT depots under normal and high-fat diet feeding, by quantifying the expression levels of 32 surface marker proteins. We observed comparable proportions of immune cells in two WAT depots under steady state, but depot-distinct subtypes of adipose precursor cells (APC), suggesting differences in their adipogenic and fibrogenic potential. Furthermore, in addition to pro-inflammatory immune cell shifts, significant pro-fibrotic changes were observed in APCs under high-fat diet, suggesting that APCs are early responders to dietary challenges. We propose CyTOF as a complementary and alternative tool to current high-throughput single-cell transcriptomic analyses to better understand the function and plasticity of adipose tissue.© 2022 The Author(s).

Early life environmental exposures can have lasting effects on the function of the immune system and contribute to disease later in life. Epidemiological studies have linked early life exposure to xenobiotics that bind the aryl hydrocarbon receptor (AhR) with dysregulated immune responses later in life. Among the immune cells influenced by developmental activation of the AhR are CD4+ T cells. Yet, the underlying affected cellular pathways via which activating the AhR early in life causes the responses of CD4+ T cells to remain affected into adulthood remain unclear.
Our goal was to identify cellular mechanisms that drive impaired CD4+ T-cell responses later in life following maternal exposure to an exogenous AhR ligand.
C57BL/6 mice were vertically exposed to the prototype AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), throughout gestation and early postnatal life. The transcriptome and DNA methylation patterns were evaluated in CD4+ T cells isolated from naïve and influenza A virus (IAV)-infected adult mice that were developmentally exposed to TCDD or vehicle control. We then assessed the influence of DNA methylation-altering drug therapies on the response of CD4+ T cells from developmentally exposed mice to infection.
Gene and protein expression showed that developmental AhR activation reduced CD4+ T-cell expansion and effector functions during IAV infection later in life. Furthermore, whole-genome bisulfite sequencing analyses revealed that developmental AhR activation durably programed DNA methylation patterns across the CD4+ T-cell genome. Treatment of developmentally exposed offspring with DNA methylation-altering drugs alleviated some, but not all, of the impaired CD4+ T-cell responses.
Taken together, these results indicate that skewed DNA methylation is one of the mechanisms by which early life exposures can durably change the function of T cells in mice. Furthermore, treatment with DNA methylation-altering drugs after the exposure restored some aspects of CD4+ T-cell functional responsiveness. https://doi.org/10.1289/EHP7699.

Autoimmune disease is 4 times more common in women than men. This bias is largely unexplained. Female skin is "autoimmunity prone," showing upregulation of many proinflammatory genes, even in healthy women. We previously identified VGLL3 as a putative transcription cofactor enriched in female skin. Here, we demonstrate that skin-directed overexpression of murine VGLL3 causes a severe lupus-like rash and systemic autoimmune disease that involves B cell expansion, autoantibody production, immune complex deposition, and end-organ damage. Excess epidermal VGLL3 drives a proinflammatory gene expression program that overlaps with both female skin and cutaneous lupus. This includes increased B cell-activating factor (BAFF), the only current biologic target in systemic lupus erythematosus (SLE); IFN-κ, a key inflammatory mediator in cutaneous lupus; and CXCL13, a biomarker of early-onset SLE and renal involvement. Our results demonstrate that skin-targeted overexpression of the female-biased factor VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease that is strikingly similar to SLE. This work strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity.

The immune microenvironment of pancreatic ductal adenocarcinoma (PDA) is comprised of a heterogeneous population of cells that are critical for disease evolution. Prominent among these are the specialized CD1dhiCD5+ regulatory B (Breg) cells that exert a pro-tumorigenic role by promoting tumor cell proliferation. Dissecting the molecular pathways regulating this immune sub-population can thus be valuable for uncovering potential therapeutic targets. Here, we investigate Bruton's tyrosine kinase (BTK), a key B-cell kinase, as a potential regulator of CD1dhiCD5+ Breg differentiation in the pancreatic tumor microenvironment. Treatment of cytokine-induced B cells in vitro with the high specificity BTK inhibitor Tirabrutinib inhibited CD1dhiCD5+ Breg differentiation and production of IL-10 and IL-35, essential mediators of Breg immunosuppressive functions. The BTK signaling pathway was also found to be active in vivo in PanIN-associated regulatory B cells. Tirabrutinib treatment of mice bearing orthotopic KrasG12D-pancreatic lesions severely compromised stromal accumulation of the CD1dhiCD5+ Breg population. This was accompanied by an increase in stromal CD8+IFNγ+ cytotoxic T cells and significant attenuation of tumor cell proliferation and PanIN growth. Our results uncover a novel role for BTK in regulating CD1dhiCD5+ Breg differentiation and emphasize its potential as a therapeutic target for pancreatic cancer.