bims-adipim Biomed News
on Adipose immunity and immunometabolism
Issue of 2023‒06‒18
seven papers selected by
Matthew C. Sinton, University of Glasgow

  1. Cells. 2023 May 26. pii: 1484. [Epub ahead of print]12(11):
      In recent decades, obesity has become one of the most common metabolic diseases [...].
  2. Proc Natl Acad Sci U S A. 2023 Jun 20. 120(25): e2300566120
      Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells which recognize a limited repertoire of ligands presented by the MHC class-I like molecule MR1. In addition to their key role in host protection against bacterial and viral pathogens, MAIT cells are emerging as potent anti-cancer effectors. With their abundance in human, unrestricted properties, and rapid effector functions MAIT cells are emerging as attractive candidates for immunotherapy. In the current study, we demonstrate that MAIT cells are potent cytotoxic cells, rapidly degranulating and inducing target cell death. Previous work from our group and others has highlighted glucose metabolism as a critical process for MAIT cell cytokine responses at 18 h. However, the metabolic processes supporting rapid MAIT cell cytotoxic responses are currently unknown. Here, we show that glucose metabolism is dispensable for both MAIT cell cytotoxicity and early (<3 h) cytokine production, as is oxidative phosphorylation. We show that MAIT cells have the machinery required to make (GYS-1) and metabolize (PYGB) glycogen and further demonstrate that that MAIT cell cytotoxicity and rapid cytokine responses are dependent on glycogen metabolism. In summary, we show that glycogen-fueled metabolism supports rapid MAIT cell effector functions (cytotoxicity and cytokine production) which may have implications for their use as an immunotherapeutic agent.
    Keywords:  MAIT cells; cytotoxicity; immunometabolism
  3. Commun Biol. 2023 Jun 13. 6(1): 638
      Autocrine and paracrine signaling regulating adipogenesis in white adipose tissue remains largely unclear. Here we used single-cell RNA-sequencing (RNA-seq) and single nuclei RNA-sequencing (snRNA-seq) to identify markers of adipose progenitor cells (APCs) and adipogenic modulators in visceral adipose tissue (VAT) of humans and mice. Our study confirmed the presence of major cellular clusters in humans and mice and established important sex and diet-specific dissimilarities in cell proportions. Here we show that bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) is a conserved marker for APCs and adipocytes in VAT in humans and mice. Further, BMPER is highly enriched in lineage negative stromal vascular cells and its expression is significantly higher in visceral compared to subcutaneous APCs in mice. BMPER expression and release peaked by day four post-differentiation in 3T3-L1 preadipocytes. We reveal that BMPER is required for adipogenesis both in 3T3-L1 preadipocytes and in mouse APCs. Together, this study identified BMPER as a positive modulator of adipogenesis.
  4. J Invest Dermatol. 2023 Jun 07. pii: S0022-202X(23)02141-3. [Epub ahead of print]
      Type 2 immune responses have been increasingly linked with tissue maintenance, regeneration and metabolic homeostasis. The molecular basis of regulator and effector mechanisms of type 2 immunity in skin regeneration and homeostasis is still lacking. Here, we analyzed the role of interleukin-4 receptor alpha (IL-4Rα) signaling in regeneration of diverse cellular compartments of the skin. Mutants with global IL-4Rα deficiency showed two major phenotypes, first a pronounced atrophy of the interfollicular epidermis (IFE) and second, a significant increase in dermal white adipose tissue (dWAT) thickness at P21 compared to littermate controls. Notably, IL-4Rα deficiency decreased activation of hormone-sensitive lipase (HSL), a rate-limiting step in lipolysis. Immunohistochemical and FACS analysis in IL-4/eGFP reporter mice showed that IL-4 expression peaked at P21 and that eosinophils are the predominant IL-4-expressing cells. Eosinophil-deficient mice recapitulated the lipolytic-defective dWAT phenotype of Il4ra-deficient mice, demonstrating that eosinophils are necessary for dWAT lipolysis. Collectively, we provide mechanistic insights into the regulation of IFE and HSL-mediated lipolysis in dWAT in early life by IL-4Rα and our findings demonstrate that eosinophils play a critical role in this process.
    Keywords:  Interleukin-4 receptor alpha; Type 2 immunity; dWAT; eosinophils; lipolysis
  5. Cancers (Basel). 2023 May 29. pii: 2963. [Epub ahead of print]15(11):
      BACKGROUND: Obesity is a well-known risk factor for cancer. We have previously reported the role of adipose-tissue-derived mesenchymal stem cells from obese individuals (ob-ASC) in the promotion of pathogenic Th17 cells and immune check point (ICP) upregulation. Thus, we postulated herein that this mechanism could contribute to breast cancer (BC) aggressiveness.METHODS: Conditioning medium (CM) from mitogen-activated ob-ASC and immune cell co-cultures were added to two human breast cancer cell line (BCCL) cultures. Expressions of pro-inflammatory cytokines, angiogenesis markers, metalloproteinases, and PD-L1 (a major ICP) were measured at the mRNA and/or protein levels. BCCL migration was explored in wound healing assays. Anti-cytokine neutralizing antibodies (Ab) were added to co-cultures.
    RESULTS: CM from ob-ASC/MNC co-cultures increased IL-1β, IL-8, IL-6, VEGF-A, MMP-9, and PD-L1 expressions in both BCCLs and accelerated their migration. The use of Abs demonstrated differential effects for IL-17A and IFNγ on BCCL pro-inflammatory cytokine over-expression or PD-L1 upregulation, respectively, but potentiating effects on BCCL migration. Finally, co-cultures with ob-ASC, but not lean ASC, enhanced PD-L1 expression.
    CONCLUSIONS: Our results demonstrate increased inflammation and ICP markers and accelerated BCCL migration following the activation of pathogenic Th17 cells by ob-ASC, which could represent a new mechanism linking obesity with BC progression.
    Keywords:  IFNγ; IL-17; PD-L1; adipose-tissue-derived mesenchymal stem cells; breast cancer; cancer progression; immune check points; obesity; pathogenic Th17 cells
  6. Immunity. 2023 Jun 13. pii: S1074-7613(23)00218-2. [Epub ahead of print]56(6): 1168-1186
      Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.
    Keywords:  cell circuits; immunometabolism; metabolism; systems immunology; tissue homeostasis; tissue-resident
  7. Front Immunol. 2023 ;14 1199233
      Reactive oxygen species (ROS) are produced both enzymatically and non-enzymatically in vivo. Physiological concentrations of ROS act as signaling molecules that participate in various physiological and pathophysiological activities and play an important role in basic metabolic functions. Diseases related to metabolic disorders may be affected by changes in redox balance. This review details the common generation pathways of intracellular ROS and discusses the damage to physiological functions when the ROS concentration is too high to reach an oxidative stress state. We also summarize the main features and energy metabolism of CD4+ T-cell activation and differentiation and the effects of ROS produced during the oxidative metabolism of CD4+ T cells. Because the current treatment for autoimmune diseases damages other immune responses and functional cells in the body, inhibiting the activation and differentiation of autoreactive T cells by targeting oxidative metabolism or ROS production without damaging systemic immune function is a promising treatment option. Therefore, exploring the relationship between T-cell energy metabolism and ROS and the T-cell differentiation process provides theoretical support for discovering effective treatments for T cell-mediated autoimmune diseases.
    Keywords:  CD4+ T cells; Th17 cells; Treg cells; effector T cells (Teffs); inflammation; reactive oxygen species