c‐Maf enforces cytokine production and promotes memory‐like responses in mouse and human type 2 innate lymphoid cells

Trabanelli, Sara; Ercolano, Giuseppe; Wyss, Tania; Gomez-Cadena, Alejandra; Falquet, Maryline; Cropp, Daniela; Imbratta, Claire; Leblond, M.M.; Salvestrini, Valentina; Curti, Antonio; Adotévi, Olivier; Jandus, Camilla; Verdeil, Grégory

doi:10.15252/embj.2021109300

Cited by 15 publications

(12 citation statements)

References 52 publications

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“…MAF, which is expressed selectively in macrophages, positively regulates IL10 production in these cells after stimulation with LPS [ 15 ]. Similarly, it has been reported that MAF induces cytokine production [ 16 ] and promotes IL10-mediated anti-inflammatory responses through inhibition of the inflammasome [ 17 ]. Finally, another recent study showed that MAF , in addition to participating in the control of IL10 production and lipogenesis, is a negative regulator of IL2, which modulates Th1, Th2 and Th17 immune responses in a context-specific manner [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

GWAS-Identified Variants for Obesity Do Not Influence the Risk of Developing Multiple Myeloma: A Population-Based Study and Meta-Analysis

Sánchez-Maldonado

Cabrera-Serrano

Chattopadhyay

et al. 2023

IJMS

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Multiple myeloma (MM) is an incurable disease characterized by the presence of malignant plasma cells in the bone marrow that secrete specific monoclonal immunoglobulins into the blood. Obesity has been associated with the risk of developing solid and hematological cancers, but its role as a risk factor for MM needs to be further explored. Here, we evaluated whether 32 genome-wide association study (GWAS)-identified variants for obesity were associated with the risk of MM in 4189 German subjects from the German Multiple Myeloma Group (GMMG) cohort (2121 MM cases and 2068 controls) and 1293 Spanish subjects (206 MM cases and 1087 controls). Results were then validated through meta-analysis with data from the UKBiobank (554 MM cases and 402,714 controls) and FinnGen cohorts (914 MM cases and 248,695 controls). Finally, we evaluated the correlation of these single nucleotide polymorphisms (SNPs) with cQTL data, serum inflammatory proteins, steroid hormones, and absolute numbers of blood-derived cell populations (n = 520). The meta-analysis of the four European cohorts showed no effect of obesity-related variants on the risk of developing MM. We only found a very modest association of the POC5rs2112347G and ADCY3rs11676272G alleles with MM risk that did not remain significant after correction for multiple testing (per-allele OR = 1.08, p = 0.0083 and per-allele OR = 1.06, p = 0.046). No correlation between these SNPs and functional data was found, which confirms that obesity-related variants do not influence MM risk.

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Section: Discussionmentioning

confidence: 99%

GWAS-Identified Variants for Obesity Do Not Influence the Risk of Developing Multiple Myeloma: A Population-Based Study and Meta-Analysis

Sánchez-Maldonado

Cabrera-Serrano

Chattopadhyay

et al. 2023

IJMS

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“…We found that the ILC2 marker genes segregating toward the top of this list, corresponding to enhanced epigenomic activity in the RAG naïve cells, tended to be genes previously identified to play positive roles in development, expansion, and activation of lymphoid cells. These included transcriptional regulators such as Tox [75][76][77][78] , Rora 38,51,[61][62][63] , Maf 19,58,59 , and Gata3 19, [50][51][52] , which are involved in early differentiation of both ILCs and lymphocytes (Fig. S9A).…”

Section: Ilc2s With a History Of Rag Expression Are Epigenomically Su...mentioning

confidence: 99%

RAG suppresses group 2 innate lymphoid cells

Ver Heul,

Mack,

Zamidar

et al. 2024

Preprint

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Antigen specificity is the central trait distinguishing adaptive from innate immune function. Assembly of antigen-specific T cell and B cell receptors occurs through V(D)J recombination mediated by the Recombinase Activating Gene endonucleases RAG1 and RAG2 (collectively called RAG). In the absence of RAG, mature T and B cells do not develop and thus RAG is critically associated with adaptive immune function. In addition to adaptive T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILC2s) contribute to type 2 immune responses by producing cytokines like Interleukin-5 (IL-5) and IL-13. Although it has been reported that RAG expression modulates the function of innate natural killer (NK) cells, whether other innate immune cells such as ILC2s are affected by RAG remains unclear. We find that in RAG-deficient mice, ILC2 populations expand and produce increased IL-5 and IL-13 at steady state and contribute to increased inflammation in atopic dermatitis (AD)-like disease. Further, we show that RAG modulates ILC2 function in a cell-intrinsic manner independent of the absence or presence of adaptive T and B lymphocytes. Lastly, employing multiomic single cell analyses of RAG1 lineage-traced cells, we identify key transcriptional and epigenomic ILC2 functional programs that are suppressed by a history of RAG expression. Collectively, our data reveal a novel role for RAG in modulating innate type 2 immunity through suppression of ILC2s.

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“…ILC2 activation is not only characterized by the secretion of type-2 cytokines and IL-10, but also by the specific production of amphiregulin (AREG), a ligand of the Epidermal Growth Factor Receptor (EGFR), which has been shown to have multiple roles in cancer progression and inflammatory responses [36][37][38] . For these reasons, we quantified AREG in CML sera at onset and observed a slight but significant increase in the patients (Supplementary Figure S4D).…”

Section: Tumor-derived Vegf-a Stimulates Ilc2 Effector Functionsmentioning

confidence: 99%

IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia

Fiordi¹,

Salvestrini²,

Gugliotta³

et al. 2023

haematol

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Chronic Myeloid Leukemia (CML) is a hematologic malignancy associated to an unregulated growth of myeloid cells in Bone Marrow (BM) and Peripheral Blood (PB), characterized by the BCR-ABL1 translocation. Given the known cytokine impairment in the leukemic niche of CML, we investigated the impact of this microenvironmental dysregulation on Innate Lymphoid Cells (ILCs), whose role in cancer has recently emerged. Three ILC subsets are identified based on transcriptional profiles and cytokine secretion. We observed that IL-18 and VEGF-A are increased in CML patients’ sera and that ILC2s are enriched in CML PB and BM. We found that IL-18 drives ILC2 proliferation and that CML ILC2s highly express CXCR4 and CXCR7 BM-homing receptors, potentially explaining their enrichment in PB and BM, respectively. Next, we showed that ILC2s are hyper-activated through a tumor-derived VEGF-A-dependent mechanism, which leads to higher IL-13 secretion. In response to IL-13, leukemic cells increase their clonogenic capacity. Finally, we discovered that the pro-tumoral axis involving VEGF-A, IL-18 and ILC2s was disrupted upon Tyrosine Kinase Inhibitors’ (TKIs) treatment, normalizing the levels of all these players in CML patients responding to therapy. Overall, our study uncovers the involvement of ILC2s in CML progression, mediated by VEGF-A and IL-18.

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c‐Maf enforces cytokine production and promotes memory‐like responses in mouse and human type 2 innate lymphoid cells

Cited by 15 publications

References 52 publications

GWAS-Identified Variants for Obesity Do Not Influence the Risk of Developing Multiple Myeloma: A Population-Based Study and Meta-Analysis

GWAS-Identified Variants for Obesity Do Not Influence the Risk of Developing Multiple Myeloma: A Population-Based Study and Meta-Analysis

RAG suppresses group 2 innate lymphoid cells

IL-18 and VEGF-A trigger type 2 innate lymphoid cell accumulation and pro-tumoral function in chronic myeloid leukemia

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