Control of lymphocyte homeostasis and effector function by the aryl hydrocarbon receptor

Wang, Hao; Wei, Yunbo; Yu, Di

doi:10.1016/j.intimp.2015.03.046

Cited by 13 publications

(8 citation statements)

References 58 publications

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“…The TCDD-induced MDSCs robustly suppressed the activation of T cells and also reduced the inflammation after Con A-induced hepatitis. Although the expression of AhR is low in many subsets of lymphocytes, the activation of AhR was able to suppress the differentiation of B cells and reduce their antibody production [ 159 ]. It seems that amino acid deprivation stimulates extensive immunosuppression through the activation of Tregs and MDSCs which subsequently suppress effector immune cells and provoke immunosenescence through the secretion of anti-inflammatory cytokines.…”

Section: Signaling Mechanisms Involved In Immunosuppression-induced Immunosenescencementioning

confidence: 99%

Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions

Salminen

2021

J Mol Med

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The functional competence of the immune system gradually declines with aging, a process called immunosenescence. The age-related remodelling of the immune system affects both adaptive and innate immunity. In particular, a chronic low-grade inflammation, termed inflammaging, is associated with the aging process. Immunosenescence not only is present in inflammaging state, but it also occurs in several pathological conditions in conjunction with chronic inflammation. It is known that persistent inflammation stimulates a counteracting compensatory immunosuppression intended to protect host tissues. Inflammatory mediators enhance myelopoiesis and induce the generation of immature myeloid-derived suppressor cells (MDSC) which in mutual cooperation stimulates the immunosuppressive network. Immunosuppressive cells, especially MDSCs, regulatory T cells (Treg), and M2 macrophages produce immunosuppressive factors, e.g., TGF-β, IL-10, ROS, arginase-1 (ARG1), and indoleamine 2,3-dioxygenase (IDO), which suppress the functions of CD4/CD8T and B cells as well as macrophages, natural killer (NK) cells, and dendritic cells. The immunosuppressive armament (i) inhibits the development and proliferation of immune cells, (ii) decreases the cytotoxic activity of CD8T and NK cells, (iii) prevents antigen presentation and antibody production, and (iv) suppresses responsiveness to inflammatory mediators. These phenotypes are the hallmarks of immunosenescence. Immunosuppressive factors are able to control the chromatin landscape, and thus, it seems that the immunosenescence state is epigenetically regulated.

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Section: Signaling Mechanisms Involved In Immunosuppression-induced Immunosenescencementioning

confidence: 99%

Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions

Salminen

2021

J Mol Med

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“…AhR can accommodate different ligands, including the carcinogenic pollutant 2,3,7,8-tétrachlorodibenzo- p -dioxine, 57 or tryptophan metabolites, as well as ligands derived from food. 58 , 59 In the absence of ligand, AhR is complexed in the cytosol with several chaperones. 60 , 61 Ligand binding induces AhR dissociation from its chaperones and its nuclear translocation, where it regulates gene expression with its canonical partner ARNT.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide CRISPR screen identifies regulation factors of the TLR3 signalling pathway

Zablocki-Thomas

Menzies²,

Lehner³

et al. 2020

Innate Immun

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A subset of TLRs is specialised in the detection of incoming pathogens by sampling endosomes for nucleic acid contents. Among them, TLR3 senses the abnormal presence of double-stranded RNA in the endosomes and initiates a potent innate immune response via activation of NF-κB and IRF3. Nevertheless, mechanisms governing TLR3 regulation remain poorly defined. To identify new molecular players involved in the TLR3 pathway, we performed a genome-wide screen using CRISPR/Cas9 technology. We generated TLR3+ reporter cells carrying a NF-κB-responsive promoter that controls GFP expression. Cells were next transduced with a single-guide RNA (sgRNA) library, subjected to sequential rounds of stimulation with poly(I:C) and sorting of the GFP-negative cells. Enrichments in sgRNA estimated by deep sequencing identified genes required for TLR3-induced activation of NF-κB. Among the hits, five genes known to be critically involved in the TLR3 pathway, including TLR3 itself and the chaperone UNC93B1, were identified by the screen, thus validating our strategy. We further studied the top 40 hits and focused on the transcription factor aryl hydrocarbon receptor (AhR). Depletion of AhR had a dual effect on the TLR3 response, abrogating IL-8 production and enhancing IP-10 release. Moreover, in primary human macrophages exposed to poly(I:C), AhR activation enhanced IL-8 and diminished IP-10 release. Overall, these results reveal AhR plays a role in the TLR3 cellular innate immune response.

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“…They revealed that the promoter of the human AhR gene contained three putative NF-κB binding sites; of these, one motif mediated the RelA/p50-induced transcription of the AhR gene which explains why an increased NF-κB signaling is associated with the stimulation of AhR signaling. Subsequently, AhR signaling is able to control the function of a large set of lymphoid cells generating either pro- or anti-inflammatory responses [ 4 , 146 ]. Moreover, bilirubin and biliverdin, the catabolic metabolites of heme protein, are also agonists of the AhR factor [ 147 ] (Fig.…”

Section: Ahr-driven Antagonistic Pleiotropy In Development and Aging ...mentioning

confidence: 99%

Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process

Salminen

2022

Cell. Mol. Life Sci.

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The antagonistic pleiotropy hypothesis is a well-known evolutionary theory to explain the aging process. It proposes that while a particular gene may possess beneficial effects during development, it can exert deleterious properties in the aging process. The aryl hydrocarbon receptor (AhR) has a significant role during embryogenesis, but later in life, it promotes several age-related degenerative processes. For instance, AhR factor (i) controls the pluripotency of stem cells and the stemness of cancer stem cells, (ii) it enhances the differentiation of embryonal stem cells, especially AhR signaling modulates the differentiation of hematopoietic stem cells and progenitor cells, (iii) it also stimulates the differentiation of immunosuppressive Tregs, Bregs, and M2 macrophages, and finally, (iv) AhR signaling participates in the differentiation of many peripheral tissues. On the other hand, AhR signaling is involved in many processes promoting cellular senescence and pathological processes, e.g., osteoporosis, vascular dysfunction, and the age-related remodeling of the immune system. Moreover, it inhibits autophagy and aggravates extracellular matrix degeneration. AhR signaling also stimulates oxidative stress, promotes excessive sphingolipid synthesis, and disturbs energy metabolism by catabolizing NAD+ degradation. The antagonistic pleiotropy of AhR signaling is based on the complex and diverse connections with major signaling pathways in a context-dependent manner. The major regulatory steps include, (i) a specific ligand-dependent activation, (ii) modulation of both genetic and non-genetic responses, (iii) a competition and crosstalk with several transcription factors, such as ARNT, HIF-1α, E2F1, and NF-κB, and (iv) the epigenetic regulation of target genes with binding partners. Thus, not only mTOR signaling but also the AhR factor demonstrates antagonistic pleiotropy in the regulation of the aging process.

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Control of lymphocyte homeostasis and effector function by the aryl hydrocarbon receptor

Cited by 13 publications

References 58 publications

Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions

Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions

A genome-wide CRISPR screen identifies regulation factors of the TLR3 signalling pathway

Aryl hydrocarbon receptor (AhR) reveals evidence of antagonistic pleiotropy in the regulation of the aging process

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