Spred1, a Suppressor of the Ras–ERK Pathway, Negatively Regulates Expansion and Function of Group 2 Innate Lymphoid Cells

Suzuki, Mayu; Morita, Rimpei; Hirata, Yasuko; Shichita, Takashi; Yoshimura, Akihiko

doi:10.4049/jimmunol.1500531

Cited by 26 publications

(21 citation statements)

References 39 publications

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“…26 Therefore the lack of IFNAR1 receptor expression might account for the inability of lung ILC2s to respond to type I interferons in the absence of IFN-g in vivo but not in vitro. Mechanistically, IFN-g did not inhibit phosphorylation of p38 and extracellular signal-regulated kinase, both of which have been shown to play prominent roles in ILC2 proliferation and cytokine production, 57,58 but increased the Socs1 mRNA level in a STAT1-dependent manner. A previous study has shown that knockdown of Socs1 enhanced mRNA and protein expression levels of IL-13 and IL-5 in ILC2s, suggesting a limiting role for this protein.…”

Section: Discussionmentioning

confidence: 84%

Toll-like receptor 9–dependent interferon production prevents group 2 innate lymphoid cell–driven airway hyperreactivity

Thio

Lai

Chi

et al. 2019

Journal of Allergy and Clinical Immunology

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Section: Discussionmentioning

confidence: 84%

Toll-like receptor 9–dependent interferon production prevents group 2 innate lymphoid cell–driven airway hyperreactivity

Thio

Lai

Chi

et al. 2019

Journal of Allergy and Clinical Immunology

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“…Our results showed that the Ras-MEK-ERK pathway plays a major role in TGF-β-mediated upregulation of ST2 in ILC2p and CHILP cells. The Ras-MEK-ERK pathway has recently been demonstrated to play an important role in the maintenance and function of ILC2s 53 . Although the detailed molecular mechanisms underlying TGF-β-mediated-regulation of ST2 remain to be elucidated, our data suggest that this might not rely on the GATA3.…”

Section: Discussionmentioning

confidence: 99%

TGF-β induces ST2 and programs ILC2 development

et al. 2020

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The molecular pathways underlying the development of innate lymphoid cells (ILCs) are mostly unknown. Here we show that TGF-β signaling programs the development of ILC2s from their progenitors. Specifically, the deficiency of TGF-β receptor II in bone marrow progenitors results in inefficient development of ILC2s, but not ILC1s or ILC3s. Mechanistically, TGF-β signaling is required for the generation and maintenance of ILC2 progenitors (ILC2p). In addition, TGF-β upregulates the expression of the IL-33 receptor gene Il1rl1 (encoding IL-1 receptor-like 1, also known as ST2) in ILC2p and common helper-like innate lymphoid progenitors (CHILP), at least partially through the MEK-dependent pathway. These findings identify a function of TGF-β in the development of ILC2s from their progenitors.

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“…Knockout mice for IL-7Ra or the common γ chain cytokine receptor lack mature ILC2s 61 indicating an important role for IL-7 in generating ILC2s in vivo. Both IL-2 and IL-7 have also been reported to help maintain ILC2 survival 13,61 while culture in combination of IL-2 and IL-7 has been used to maintain ILC2s isolated from lung or Lin −ve ILC progenitors from bone marrow 62,63 . Mesenteric fat ILC2s maintained a Lin −ve /CD45 +ve / Sca1 +ve /KLRG1 +ve phenotype characteristic of ILC2s during culture.…”

Section: Discussionmentioning

confidence: 99%

p38 MAPK signalling regulates cytokine production in IL-33 stimulated Type 2 Innate Lymphoid cells

Petrova

Pesic

Pardali

et al. 2020

Sci Rep

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Type 2 Innate lymphoid cells (ILC2s) are implicated in helminth infections and asthma where they play a role in the production of Th2-type cytokines. ILC2s express the IL-33 receptor and are a major cell type thought to mediate the effects of this cytokine in vivo. To study the signalling pathways that mediate IL-33 induced cytokine production, a culture system was set up to obtain pure populations of ILC2s from mice. Inhibitors of the p38α/β and ERK1/2 MAPK pathways reduced the production of IL-5, IL-6, IL-9, IL-13 and GM-CSF by ILC2 in response to IL-33, with inhibition of p38 having the greatest effect. MK2 and 3 are kinases activated by p38α; MK2/3 inhibitors or knockout of MK2/3 in mice reduced the production of IL-6 and IL-13 (two cytokines implicated in asthma) but not IL-5, IL-9 or GM-CSF in response to IL-33. MK2/3 inhibition also suppressed IL-6 and IL-13 production by human ILC2s. MK2/3 were required for maximal S6 phosphorylation, suggesting an input from the p38α-MK2/3 pathway to mTOR1 activation in ILC2s. The mTORC1 inhibitor rapamycin also reduced IL-6 and IL-13 production, which would be consistent with a model in which MK2/3 regulate IL-6 and IL-13 via mTORC1 activation in ILC2s.Innate lymphoid cells (ILCs) are a recently identified group of lymphocytes acting within the innate immune system. ILCs lack antigen specific receptors, however in terms of the cytokines they produce they mimic various Th cell subsets. ILCs are found in both lymphoid and non-lymphoid tissues, particularly at the barrier sites including skin, respiratory and gastrointestinal systems 1-4 . Based on their effector function, cell surface markers and the transcription factors required for their development, ILCs can be subdivided into several distinct groups 1,2 . Group 1 includes NK cells and ILC1 cells, which are involved in protective immunity to viral infections and antimicrobial responses. The second group comprises of type 2 innate lymphoid cells (ILC2). ILC2 cells secrete type two cytokines and are implicated in responses to helminth infection, asthma and atopic diseases. The third group includes the lymphoid tissue inducer cells and ILC3. In 2017, a potential new group of ILC with regulatory functions was discovered. ILCreg are found in human and mouse gut and limit the activity of ILC1 and ILC3 by secreting the anti-inflammatory cytokine IL-10 5 .The first evidence for the existence of ILC2 cells was found in 2006 when Fallon et al. showed that during infection with the helminth Nippostrongylus brasilienis a population of non-T and non-B cells secrete IL-4, IL-5 and IL-13 and promote helminth expulsion 6 . In 2010, several labs reported the characterisation of ILC2s as a distinct population of cells, which were initially referred to as either neuocytes, innate helper 2 cells or natural helper cells 7-9 . ILC2s are found in the lymphoid tissues such as spleen and mesenteric lymph nodes, as well as in some non-lymphoid organs including fat associated lymphoid clusters, lungs, skin and liver. In mice, ILC2 are character...

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Spred1, a Suppressor of the Ras–ERK Pathway, Negatively Regulates Expansion and Function of Group 2 Innate Lymphoid Cells

Cited by 26 publications

References 39 publications

Toll-like receptor 9–dependent interferon production prevents group 2 innate lymphoid cell–driven airway hyperreactivity

Toll-like receptor 9–dependent interferon production prevents group 2 innate lymphoid cell–driven airway hyperreactivity

TGF-β induces ST2 and programs ILC2 development

p38 MAPK signalling regulates cytokine production in IL-33 stimulated Type 2 Innate Lymphoid cells

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