IL13Rα2 expression identifies tissue‐resident IL‐22‐producing PLZF<sup>+</sup> innate T cells in the human liver

Paquin‐Proulx, Dominic; Greenspun, Benjamin C.; Pasquet, Lise; Strunz, Benedikt; Aleman, Soo; Falconer, Karolin; Terabe, Masaki; Berzofsky, Jay A.; Sandberg, Johan K.; Melum, Espen; Nixon, Douglas F.; Björkström, Niklas K.

doi:10.1002/eji.201747334

Cited by 6 publications

(6 citation statements)

References 35 publications

(44 reference statements)

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“…Since YKL‐40 is highly expressed in GCA lesions, we next investigated the expression of IL‐13Rα2, a confirmed receptor for YKL‐40 ( 24 , 25 ), in inflamed temporal artery biopsy specimens from GCA patients (n = 12). IHC detection revealed high expression of IL‐13Rα2 by endothelial cells, infiltrating leukocytes, vascular smooth muscle cells, and fibroblasts (Figure 4A ), which is consistent with previous reports in the literature ( 19 , 25 , 29 , 30 , 31 ). Semiquantitative scoring of IL‐13Rα2 staining demonstrated high expression levels in all 3 layers of the vessel wall, most prominently in the adventitia and media‐intima borders (Figure 4B ).…”

Section: Resultssupporting

confidence: 90%

A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL‐40/Interleukin‐13 Receptor α2 Axis

Sleen

Jiemy

Pringle

et al. 2021

Arthritis & Rheumatology

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Objective. Macrophages mediate inflammation, angiogenesis, and tissue destruction in giant cell arteritis (GCA). Serum levels of the macrophage-associated protein YKL-40 (chitinase 3-like protein 1), previously linked to angiogenesis and tissue remodeling, remain elevated in GCA despite glucocorticoid treatment. This study was undertaken to investigate the contribution of YKL-40 to vasculopathy in GCA.Methods. Immunohistochemistry was performed on GCA temporal artery biopsy specimens (n = 12) and aortas (n = 10) for detection of YKL-40, its receptor interleukin-13 receptor α2 (IL-13Rα2), macrophage markers PU.1 and CD206, and the tissue-destructive protein matrix metalloproteinase 9 (MMP-9). Ten noninflamed temporal artery biopsy specimens served as controls. In vitro experiments with granulocyte-macrophage colony-stimulating factor (GM-CSF)-or macrophage colony-stimulating factor (M-CSF)-skewed monocyte-derived macrophages were conducted to study the dynamics of YKL-40 production. Next, small interfering RNA-mediated knockdown of YKL-40 in GM-CSF-skewed macrophages was performed to study its effect on MMP-9 production. Finally, the angiogenic potential of YKL-40 was investigated by tube formation experiments using human microvascular endothelial cells (HMVECs).Results. YKL-40 was abundantly expressed by a CD206+MMP-9+ macrophage subset in inflamed temporal arteries and aortas. GM-CSF-skewed macrophages from GCA patients, but not healthy controls, released significantly higher levels of YKL-40 compared to M-CSF-skewed macrophages (P = 0.039). In inflamed temporal arteries, IL-13Rα2 was expressed by macrophages and endothelial cells. Functionally, knockdown of YKL-40 led to a 10-50% reduction in MMP-9 production by macrophages, whereas exposure of HMVECS to YKL-40 led to significantly increased tube formation. Conclusion.In GCA, a GM-CSF-skewed, CD206+MMP-9+ macrophage subset expresses high levels of YKL-40 which may stimulate tissue destruction and angiogenesis through IL-13Rα2 signaling. Targeting YKL-40 or GM-CSF may inhibit macrophages that are currently insufficiently suppressed by glucocorticoids.

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Section: Resultssupporting

confidence: 90%

A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL‐40/Interleukin‐13 Receptor α2 Axis

Sleen

Jiemy

Pringle

et al. 2021

Arthritis & Rheumatology

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“…In AIH, numbers of intrahepatic sulfatide-reactive type II NKT cells are increased and they represent about 3.8% of intrahepatic leukocytes. Apart from our group, others have also detected sulfatide-reactive type II NKT cells in human peripheral blood, intestinal mucosa and livers (37–39).…”

Section: Discussionmentioning

confidence: 56%

“…Another well-established example for type II NKT cells adopting a more pro-inflammatory role is in inflammatory bowel disease, both in mouse models and in human ulcerative colitis (38, 45, 46). Interestingly, sulfatide-reactive IL-13Ralpha2+ type II NKT are enriched in the lamina propria of human ulcerative colitis and IL-13Ralpha2+ cells have also been recently identified in human liver (38, 39). In our analyses, type II NKT cell numbers and their cytokine profile were independent of whether AIH patients were treated immuno-suppressively or were treatment-naive.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Phenotype of Intrahepatic Sulfatide-Reactive Type II NKT Cells in Humans With Autoimmune Hepatitis

et al. 2019

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Background: Natural Killer T (NKT) cells are CD1d-restricted innate-like T cells that can rapidly release stored cytokines upon recognition of lipid antigens. In mice, type I NKT cells seem to promote liver inflammation, whereas type II NKT cells seem to restrict hepatitis. Here, we aimed at characterizing the role of human type I and type II NKT in patients with autoimmune hepatitis (AIH). Methods: NKT cells were analyzed by flow cytometry in peripheral blood and liver of AIH patients and control groups. α-galactosylceramide-loaded or sulfatide-loaded tetramers were used to detect type I or II NKT cells, respectively. Hepatic CD1d was stained by in situ -hybridization of liver biopsies. Results and Conclusions: Type II NKT cells were more prevalent in human peripheral blood and liver than type I NKT cells. In AIH patients, the frequency of sulfatide-reactive type II NKT cells was significantly increased in peripheral blood (0.11% of peripheral blood leukocytes) and liver (3.78% of intrahepatic leukocytes) compared to healthy individuals (0.05% and 1.82%) and patients with drug-induced liver injury (0.06% and 2.03%; p < 0.05). Intrahepatic type II NKT cells of AIH patients had a different cytokine profile than healthy subjects with an increased frequency of TNFα (77.8% vs. 59.1%, p < 0.05), decreased IFNγ (32.7% vs. 63.0%, p < 0.05) and a complete lack of IL-4 expressing cells (0% vs. 2.1%, p < 0.05). T cells in portal tracts expressed significantly more CD1d-RNA in AIH livers compared to controls. This study supports that in contrast to their assumed protective role in mice, human intrahepatic, sulfatide-reactive type II NKT cells displayed a proinflammatory cytokine profile in patients with AIH. Infiltrating T cells in portal areas of AIH patients overexpressed CD1d and could thereby activate type II NKT cells.

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“…In another study, type II NKT cells inhibited alcohol-induced liver disease in a similar manner ( 72 ). Interestingly, sulfatide-reactive type II NKT cells that express IL-13Rα2 were detected in human liver and suggested to play a role in the protection from liver fibrosis ( 73 ). Thus, sulfatide activated type II NKT cells regulate pro-inflammatory type I NKT cells in liver inflammation.…”

Section: Type II Nkt Cells In Different Diseasesmentioning

confidence: 99%

Type II NKT Cells: An Elusive Population With Immunoregulatory Properties

2018

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Natural killer T (NKT) cells are unique unconventional T cells that are reactive to lipid antigens presented on the non-polymorphic major histocompatibility class (MHC) I-like molecule CD1d. They have characteristics of both innate and adaptive immune cells, and have potent immunoregulatory roles in tumor immunity, autoimmunity, and infectious diseases. Based on their T cell receptor (TCR) expression, NKT cells are divided into two subsets, type I NKT cells with an invariant TCRα-chain (Vα24 in humans, Vα14 in mice) and type II NKT cells with diverse TCRs. While type I NKT cells are well-studied, knowledge about type II NKT cells is still limited, and it is to date only possible to identify subsets of this population. However, recent advances have shown that both type I and type II NKT cells play important roles in many inflammatory situations, and can sometimes regulate the functions of each other. Type II NKT cells can be both protective and pathogenic. Here, we review current knowledge on type II NKT cells and their functions in different disease settings and how these cells can influence immunological outcomes.

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IL13Rα2 expression identifies tissue‐resident IL‐22‐producing PLZF⁺ innate T cells in the human liver

Cited by 6 publications

References 35 publications

A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL‐40/Interleukin‐13 Receptor α2 Axis

A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL‐40/Interleukin‐13 Receptor α2 Axis

Inflammatory Phenotype of Intrahepatic Sulfatide-Reactive Type II NKT Cells in Humans With Autoimmune Hepatitis

Type II NKT Cells: An Elusive Population With Immunoregulatory Properties

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IL13Rα2 expression identifies tissue‐resident IL‐22‐producing PLZF+ innate T cells in the human liver

Cited by 6 publications

References 35 publications

A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL‐40/Interleukin‐13 Receptor α2 Axis

A Distinct Macrophage Subset Mediating Tissue Destruction and Neovascularization in Giant Cell Arteritis: Implication of the YKL‐40/Interleukin‐13 Receptor α2 Axis

Inflammatory Phenotype of Intrahepatic Sulfatide-Reactive Type II NKT Cells in Humans With Autoimmune Hepatitis

Type II NKT Cells: An Elusive Population With Immunoregulatory Properties

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IL13Rα2 expression identifies tissue‐resident IL‐22‐producing PLZF⁺ innate T cells in the human liver