IL-25 Inhibits Atherosclerosis Development in Apolipoprotein E Deficient Mice

Mantani, Polyxeni T.; Dunér, Pontus; Bengtsson, Eva; Alm, Ragnar; Ljungcrantz, Irena; Söderberg, Ingrid; Sundius, Lena; To, Fong; Nilsson, Jan; Björkbacka, Harry; Fredrikson, Gunilla Nordin

doi:10.1371/journal.pone.0117255

Cited by 41 publications

(53 citation statements)

References 36 publications

(66 reference statements)

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“…Thus, ILC2s represent an early source of these cytokines in type 2 immune responses. In line with the above, we have previously shown that IL-25 treatment of apoE-deficient mice (Apoe Ϫ/Ϫ ) reduces atherosclerosis through expansion of IL-5-releasing ILC2s, leading to increased levels of atheroprotective B1a-derived IgM antibodies recognizing the oxidized LDL epitope phosphorylcholine (PC) (28). Nevertheless, the biological significance of endogenous IL-25 in atherosclerosis remains an unanswered question.…”

mentioning

confidence: 72%

“…Interestingly, IL-25 deficiency reduced splenic ILC2s, as assessed with the use of a flow cytometry (Lin Ϫ CD45 ϩ IL-17RB ϩ ICOS ϩ IL-7ra intermediate ), a cell type that previously has been shown to have atheroprotective properties ( Fig. 4e) (28). No differences in Th2 cells were detected (Fig.…”

Section: Il-25 Deficiency or Il-25 Blockade Shifts The Cytokine Balanmentioning

confidence: 84%

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Interleukin-25 (IL-25) has a protective role in atherosclerosis development in the aortic arch in mice

Mantani¹,

Dunér²,

Bengtsson

et al. 2018

Journal of Biological Chemistry

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Atherosclerosis is a chronic inflammatory disease characterized by the entrapment of apolipoprotein B-containing lipoproteins in the arterial intima, leading to local inflammation. T helper (Th) cell 1-mediated immune responses have been associated with atherosclerosis, and the cytokine interleukin-25 (IL-25 or IL-17E) has been reported to potentially regulate Th1 cell- and Th17 cell-related immune responses. In this study, we evaluated the effects of complete IL-25 deficiency or of a temporal IL-25 blockade on atherosclerosis development in apolipoprotein E-deficient () mice. Mice deficient in both apolipoprotein E and IL-25 () had more Th1 cells in the spleen, along with elevated plasma levels of IL-17 and an increased release of splenic interferon-γ (INF-γ). In support of this observation, a 4-week-long treatment of young mice (at 10-14 weeks of age) with an IL-25-blocking antibody increased the release of Th1/Th17-associated cytokines in the spleen. In both mouse models, these findings were associated with increased atherosclerotic plaque formation in the aortic arch. We conclude that complete IL-25 deficiency and a temporal IL-25 blockade during early plaque development aggravate atherosclerosis development in the aortic arch of mice, accompanied by an increase in Th1/Th17-mediated immune responses. Our finding that endogenous IL-25 has an atheroprotective role in the murine aortic arch has potential implications for atherosclerosis development and management in humans.

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mentioning

confidence: 72%

Section: Il-25 Deficiency or Il-25 Blockade Shifts The Cytokine Balanmentioning

confidence: 84%

Interleukin-25 (IL-25) has a protective role in atherosclerosis development in the aortic arch in mice

Mantani¹,

Dunér²,

Bengtsson

et al. 2018

Journal of Biological Chemistry

Self Cite

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“…Previous studies suggested a potential role for ILC2 in the modulation of atherosclerosis2326. However, those studies used immune-compromised animals and relied on non-physiological exogenous and chronic administration of cytokines (that is, IL-2 and IL-25) that are not specific for the ILC2 population, and that can promote ILC2-independent immune responses.…”

Section: Discussionmentioning

confidence: 99%

Type-2 innate lymphoid cells control the development of atherosclerosis in mice

et al. 2017

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Type-2 innate lymphoid cells (ILC2) are a prominent source of type II cytokines and are found constitutively at mucosal surfaces and in visceral adipose tissue. Despite their role in limiting obesity, how ILC2s respond to high fat feeding is poorly understood, and their direct influence on the development of atherosclerosis has not been explored. Here, we show that ILC2 are present in para-aortic adipose tissue and lymph nodes and display an inflammatory-like phenotype atypical of adipose resident ILC2. High fat feeding alters both the number of ILC2 and their type II cytokine production. Selective genetic ablation of ILC2 in Ldlr−/− mice accelerates the development of atherosclerosis, which is prevented by reconstitution with wild type but not Il5−/− or Il13−/− ILC2. We conclude that ILC2 represent a major innate cell source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet.

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“…For example, NK cells, a kind of cytotoxic IFN‐γ–secreting innate cells that are phenotypically related to the ILC1 subset, could accelerate AS lesion development in mice . IL‐25‐producing and IL‐33‐producing ILC2 cells have been shown to reduce AS . In addition, it has been shown that transcription factor Id3 could regulate the IL‐5 production of Lin−Sca1+CD117+CD90+ ILCs present in the aorta of AS mice .…”

Section: Discussionmentioning

confidence: 99%

Type 1 innate lymphoid cell aggravation of atherosclerosis is mediated through TLR4

Liu

et al. 2018

Scand J Immunol

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ILC populations elaborate a similar cytokine expression pattern with helper T cell subsets Th1, Th2 and Th17. Recent studies indicate that CD25+ILC2 could alleviate atherosclerosis by altering lipid metabolism, whereas the depletion of CD90-expressing ILCs had no influence on atherosclerosis. Thus, these findings raise the question of whether ILC1 cells react on atherosclerosis. Hence, our group attempted to explore the role of ILC1 cells in atherosclerosis. We found that ILC1 cells have a high Th1-like gene expression of T-bet and IFN-γ, which is distinct from ILC2, ILC3 or conventional NK (cNK) cells. Moreover, atherosclerotic lesions were greatly reduced in ApoE-/-Rag1-/- mice treated with anti-NK1.1 mAbs for depleting ILC1 cells (ILC1+cNK cells), compared to ApoE-/-Rag1-/- mice treated with anti-IL-15R mAbs for depleting cNK cells, and these effects could be fully rescued through the adoptive transfer of ILC1 cells sorted from the spleen of ApoE-/-TLR4+/+ mice into ApoE-/-Rag1-/- mice treated with anti-NK1.1 mAbs. However, the adoptive transfer of ILC1 cells sorted from the spleen of ApoE-/-TLR4-/- mice into ApoE-/-Rag1-/- mice treated with anti-NK1.1 mAbs blocked the progression of atherosclerosis, indicating that the pro-atherosclerotic role of ILC1 cells is dependent on TLR4. Furthermore, oxLDL-induced increase in IFN-γ expression from ApoE-/- ILC1 cells was correlated with the decrease in BACH2 expression. Taken together, ILC1 cells exist in atherosclerosis and aggravate atherosclerosis via increasing pro-inflammatory cytokine expression in a TLR4/BACH2-dependent manner.

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IL-25 Inhibits Atherosclerosis Development in Apolipoprotein E Deficient Mice

Cited by 41 publications

References 36 publications

Interleukin-25 (IL-25) has a protective role in atherosclerosis development in the aortic arch in mice

Interleukin-25 (IL-25) has a protective role in atherosclerosis development in the aortic arch in mice

Type-2 innate lymphoid cells control the development of atherosclerosis in mice

Type 1 innate lymphoid cell aggravation of atherosclerosis is mediated through TLR4

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