bims-adipim Biomed News
on Adipose immunity and immunometabolism
Issue of 2023‒07‒02
ten papers selected by
Matthew C. Sinton, University of Glasgow

  1. Front Immunol. 2023 ;14 1233791
    Keywords:  adipose tissue macrophages; innate immunity; metabolic diseases; metabolism; obesity; phenotype; plasticity; therapeutic target
  2. Int J Mol Sci. 2023 Jun 09. pii: 9953. [Epub ahead of print]24(12):
      Currently, one-third of people worldwide are overweight or obese, with a higher prevalence in women than in men and in the elderly than in the young [...].
  3. Clin Exp Immunol. 2023 Jun 27. pii: uxad068. [Epub ahead of print]
      IL-17A+ CD8+ T-cells, termed Tc17 cells, have been identified at sites of inflammation in several immune-mediated inflammatory diseases. However, the biological function of human IL-17A+ CD8+ T-cells is not well-characterised, likely due in part to the relative scarcity of these cells. Here we expanded IL-17A+ CD8+ T-cells from healthy donor PBMC or bulk CD8+ T-cell populations using an in vitro polarisation protocol. We show that T-cell activation in the presence of IL-1β and IL-23 significantly increased the frequencies of IL-17A+ CD8+ T-cells, which was not further enhanced by IL-6, IL-2 or anti-IFNγ mAb addition. In vitro-generated IL-17A+ CD8+ T-cells displayed a distinct type-17 profile compared with IL-17A- CD8+ T-cells, as defined by transcriptional signature (IL17A, IL17F, RORC, RORA, MAF, IL23R, CCR6); high surface expression of CCR6 and CD161; and polyfunctional production of IL-17A, IL-17F, IL-22, IFNγ, TNFα and GM-CSF. A significant proportion of in vitro-induced IL-17A+ CD8+ T-cells expressed TCRVα7.2 and bound MR1 tetramers indicative of MAIT cells, indicating that our protocol expanded both conventional and unconventional IL-17A+ CD8+ T-cells. Using an IL-17A secretion assay, we sorted the in vitro-generated IL-17A+ CD8+ T-cells for functional analysis. Both conventional and unconventional IL-17A+ CD8+ T-cells were able to induce pro-inflammatory IL-6 and IL-8 production by synovial fibroblasts from patients with psoriatic arthritis, which was reduced upon addition of anti-TNFα and anti-IL-17A neutralising antibodies. Collectively, these data demonstrate that human in vitro-generated IL-17A+ CD8+ T-cells are biologically functional and that their pro-inflammatory function can be targeted, at least in vitro, using existing immunotherapy.
    Keywords:  IL-17A; IL-17F; MAIT cells; Tc17 cells; fibroblasts; psoriatic arthritis
  4. Int J Mol Sci. 2023 Jun 18. pii: 10305. [Epub ahead of print]24(12):
      The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in host defence against microbial organisms and the development of inflammatory diseases, including psoriasis (PsO), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA). IL-17A is the signature cytokine produced by T helper 17 (Th17) cells and is considered the most biologically active form. The pathogenetic involvement of IL-17A in these conditions has been confirmed, and its blockade with biological agents has provided a highly effective therapeutical approach. IL-17F is also overexpressed in the skin and synovial tissues of patients with these diseases, and recent studies suggest its involvement in promoting inflammation and tissue damage in axSpA and PsA. The simultaneous targeting of IL-17A and IL-17F by dual inhibitors and bispecific antibodies may improve the management of Pso, PsA, and axSpA, as demonstrated in the pivotal studies of dual specific antibodies such as bimekizumab. The present review focuses on the role of IL-17F and its therapeutic blockade in axSpA and PsA.
    Keywords:  axial spondyloarthritis; bimekizumab; interleukin 17F; psoriasis; psoriatic arthritis; sonelokimab
  5. Nat Commun. 2023 Jun 30. 14(1): 3878
      Interleukin (IL)-26 is a TH17 cytokine with known antimicrobial and pro-inflammatory functions. However, the precise role of IL-26 in the context of pathogenic TH17 responses is unknown. Here we identify a population of blood TH17 intermediates that produce high levels of IL-26 and differentiate into IL-17A-producing TH17 cells upon TGF-β1 exposure. By combining single cell RNA sequencing, TCR sequencing and spatial transcriptomics we show that this process occurs in psoriatic skin. In fact, IL-26+ TH17 intermediates infiltrating psoriatic skin induce TGF-β1 expression in basal keratinocytes and thereby promote their own differentiation into IL-17A-producing cells. Thus, our study identifies IL-26-producing cells as an early differentiation stage of TH17 cells that infiltrates psoriatic skin and controls its own maturation into IL17A-producing TH17 cells, via epithelial crosstalk involving paracrine production of TGF-β1.
  6. Cells. 2023 06 08. pii: 1583. [Epub ahead of print]12(12):
      The immune and endocrine dysfunctions of white adipose tissue are a hallmark of metabolic disorders such as obesity and type 2 diabetes. In humans, white adipose tissue comprises distinct depots broadly distributed under the skin (hypodermis) and as internal depots (visceral). Depot-specific ASCs could account for visceral and subcutaneous adipose tissue properties, by regulating adipogenesis and immunomodulation. More importantly, visceral and subcutaneous depots account for distinct contributions to obesity and its metabolic comorbidities. Recently, distinct ASCs subpopulations were also described in subcutaneous adipose tissue. Interestingly, the superficial layer closer to the dermis shows hyperplastic and angiogenic capacities, whereas the deep layer is considered as having inflammatory properties similar to visceral. The aim of this focus review is to bring the light of recent discoveries into white adipose tissue heterogeneity together with the biology of distinct ASCs subpopulations and to explore adipose tissue 3D models revealing their advantages, disadvantages, and contributions to elucidate the role of ASCs in obesity development. Recent advances in adipose tissue organoids opened an avenue of possibilities to recreate the main cellular and molecular events of obesity leading to a deep understanding of this inflammatory disease besides contributing to drug discovery. Furthermore, 3D organ-on-a-chip will add reproducibility to these adipose tissue models contributing to their translation to the pharmaceutical industry.
    Keywords:  3D culture; adipose stem/stromal cells; adipose tissue; obesity; organoids; spheroids
  7. Int J Mol Sci. 2023 Jun 14. pii: 10132. [Epub ahead of print]24(12):
      Mesenchymal stromal cells (MSC) show promise as cellular therapeutics. Psoriasis is a chronic inflammatory disease affecting the skin and the joints. Injury, trauma, infection and medications can trigger psoriasis by disrupting epidermal keratinocyte proliferation and differentiation, which activates the innate immune system. Pro-inflammatory cytokine secretion drives a T helper 17 response and an imbalance of regulatory T cells. We hypothesized that MSC adoptive cellular therapy could immunomodulate and suppress the effector T cell hyperactivation that underlies the disease. We used the imiquimod-induced psoriasis-like skin inflammation model to study the therapeutic potential of bone marrow and adipose tissue-derived MSC in vivo. We compared the secretome and the in vivo therapeutic potential of MSC with and without cytokine pre-challenge ("licensing"). The infusion of both unlicensed and licensed MSC accelerated the healing of psoriatic lesions, and reduced epidermal thickness and CD3+ T cell infiltration while promoting the upregulation of IL-17A and TGF-β. Concomitantly, the expression of keratinocyte differentiation markers in the skin was decreased. However, unlicensed MSC promoted the resolution of skin inflammation more efficiently. We show that MSC adoptive therapy upregulates the transcription and secretion of pro-regenerative and immunomodulatory molecules in the psoriatic lesion. Accelerated healing is associated with the secretion of TGF-β and IL-6 in the skin and MSC drives the production of IL-17A and restrains T-cell-mediated pathology.
    Keywords:  IL-17A; IL-6; MSC secretome; TGF-β; chemokines; cytokines; mesenchymal stromal cell; psoriasis
  8. Physiol Behav. 2023 Jun 25. pii: S0031-9384(23)00205-6. [Epub ahead of print]269 114280
      BACKGROUND: Melanocortin 4 receptor (MC4R) activity in the hypothalamus is crucial for regulation of metabolism and food intake. The peptide ligands for the MC4R are associated with feeding, energy expenditure, and also with complex behaviors that orchestrate energy intake and expenditure, but the downstream neuroanatomical and neurochemical targets associated with these behaviors are elusive. In addition to strong expression in the hypothalamus, the MC4R is highly expressed in the medial prefrontal cortex, a region involved in executive function and decision-making.METHODS: Using viral techniques in genetically modified male mice combined with molecular techniques, we identify and define the effects on feeding behavior of a novel population of MC4R expressing neurons in the infralimbic (IL) region of the cortex.
    RESULTS: Here, we describe a novel population of MC4R-expressing neurons in the IL of the mouse prefrontal cortex that are glutamatergic, receive input from melanocortinergic neurons, and project to multiple regions that coordinate appetitive responses to food-related stimuli. The neurons are stimulated by application of MC4R-specific peptidergic agonist, THIQ. Deletion of MC4R from the IL neurons causes increased food intake and body weight gain and impaired executive function in simple food-related behavior tasks.
    CONCLUSION: Together, these data suggest that MC4R neurons of the IL play a critical role in the regulation of food intake in male mice.
    Keywords:  MC4R; eating behavior; food intake; food-seeking; infralimbic cortex; obesity
  9. J Exp Med. 2023 10 02. pii: e20221911. [Epub ahead of print]220(10):
      Th17 cells play a critical role in both tissue homeostasis and inflammation during clearance of infections as well as autoimmune and inflammatory disorders. Despite numerous efforts to distinguish the homeostatic and inflammatory roles of Th17 cells, the mechanism underlying the divergent functions of inflammatory Th17 cells remains poorly understood. In this study, we demonstrate that the inflammatory Th17 cells involved in autoimmune colitis and those activated during colitogenic infection are distinguishable populations characterized by their differential responses to the pharmacological molecule, clofazimine (CLF). Unlike existing Th17 inhibitors, CLF selectively inhibits proautoimmune Th17 cells while preserving the functional state of infection-elicited Th17 cells partially by reducing the enzyme ALDH1L2. Overall, our study identifies two distinct subsets within the inflammatory Th17 compartment with distinct regulatory mechanisms. Furthermore, we highlight the feasibility to develop disease-promoting Th17 selective inhibitor for treating autoimmune diseases.
  10. Cell Rep. 2023 Jun 23. pii: S2211-1247(23)00695-2. [Epub ahead of print]42(7): 112684
      γδ T cells make key contributions to tissue physiology and immunosurveillance through two main functionally distinct subsets, γδ T1 and γδ T17. m6A methylation plays critical roles in controlling numerous aspects of mRNA metabolism that govern mRNA turnover, gene expression, and cellular functional specialization; however, its role in γδ T cells remains less well understood. Here, we find that m6A methylation controls the functional specification of γδ T17 vs. γδ T1 cells. Mechanistically, m6A methylation prevents the formation of endogenous double-stranded RNAs and promotes the degradation of Stat1 transcripts, which converge to prevent over-activation of STAT1 signaling and ensuing inhibition of γδ T17. Deleting Mettl3, the key enzyme in the m6A methyltransferases complex, in γδ T cells reduces interleukin-17 (IL-17) production and ameliorates γδ T17-mediated psoriasis. In summary, our work shows that METTL3-mediated m6A methylation orchestrates mRNA stability and double-stranded RNA (dsRNA) contents to equilibrate γδ T1 and γδ T17 cells.
    Keywords:  CP: Immunology; CP: Molecular biology; IL-17; m6A methylation; psoriasis; γδ T cells