Histone deacetylase 1 controls CD4+ T cell trafficking in autoinflammatory diseases

Hamminger, Patricia; Marchetti, Luca; Preglej, Teresa; Platzer, René; Zhu, Ci; Kamnev, Anton; Rica, Ramona; Stolz, Valentina; Sandner, Lisa; Alteneder, Marlis; Kaba, Elisa; Waltenberger, Darina; Huppa, Johannes B.; Trauner, Michael; Bock, Christoph; Lyck, Ruth; Bauer, Jan; Dupré, Loïc; Seiser, Christian; Boucheron, Nicole; Engelhardt, Britta; Ellmeier, Wilfried

doi:10.1016/j.jaut.2021.102610

Cited by 8 publications

(11 citation statements)

References 68 publications

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“…Having shown that the inhibition of the catalytic activity of HDAC1 in T cells is sufficient to protect mice from EAE, we next wanted to understand the impact of HDAC1 Off and HDAC1 On expression on the transcriptomes of in vivo activated antigen-specific CD4 + T cells. In order to do so, we followed a protocol that we previously applied to investigate transcriptomes of in vivo activated WT and HDAC1 cKO CD4 + T cells [27]. We crossed HDAC1 On and HDAC1 Off mice with 2D2 TCR transgenic mice that express a TCR (formed by Vα3.2 and Vβ11) specific for MOG35-55 peptide [29].…”

Section: Impact Of Hdac1 Catalytic Activity Inactivation On Gene Expr...mentioning

confidence: 99%

“…We have recently shown that conditional knockout mice lacking HDAC1 in T cells (using the Cd4-Cre deleter strain; Hdac1 fl/fl x Cd4-Cre; HDAC1 cKO ) are protected from EAE disease development [26]. We further revealed that HDAC1 is an important regulator for T cell trafficking in EAE, since HDAC1-deficient CD4 + T cells fail to migrate into the CNS [27]. These results suggest that HDAC1 might be a suitable target for treating autoimmune CNS diseases including MS.…”

Section: Introductionmentioning

confidence: 96%

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Targeting the catalytic activity of HDAC1 in T cells protects against experimental autoimmune encephalomyelitis

Zhu

Stolz

Simonovic

et al. 2023

Preprint

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Histone deacetylases are key epigenetic regulators that control T cell-mediated immunity. A T cell-specific deletion ofHdac1(HDAC1cKO) protects mice against experimental autoimmune encephalomyelitis (EAE). However, it remains elusive whether inhibition of HDAC1 enzymatic activity, which could be achieved therapeutically by HDAC1 inhibitor treatment, is sufficient to block EAE induction. In order to address this question, we generated a novel mouse strain that expresses catalytically inactive HDAC1 (HDAC1Off) from theRosa26locus in HDAC1cKOCD4+T cells to mimic selective inhibition of HDAC1 enzymatic activityin vivo. Mice expressing wildtype HDAC1 in HDAC1cKOCD4+T cells (HDAC1On) were generated as corresponding controls. In contrast to HDAC1Onmice, HDAC1Offmice did not develop EAE, and this correlated with diminished leukocyte CNS infiltration. HDAC1OffCD4+T cells in the CNS displayed a severe reduction of IFNγ, IL-17A and TNFα proinflammatory cytokine expression, andin vivoactivated HDAC1OffCD4+T cells downregulated gene sets associated with T cell activation, cytokine expression and cell migration. This indicates impaired effector functions of HDAC1OffCD4+T cells. Taken together, our study demonstrates that the inhibition of the catalytic activity of HDAC1 in T cells is sufficient to achieve a clinical benefit in EAE disease development. This raises the translational perspective of pharmacological HDAC1 inhibition for treating human T cell-mediated autoimmune diseases.HighlightsSuccessful generation of a novel mouse model that expresses enzymatic-inactive HDAC1 to mimic HDAC1 inhibitor treatmentin vivo.Mice expressing enzymatically inactive HDAC1 instead of WT HDAC1 in T cells do not develop EAE and display diminished leukocyte CNS infiltration.In vivoactivated CD4+T cells expressing enzymatic inactive HDAC1 downregulate pathways important for T cell activation, cytokine expression and cell migration.Demonstrate the proof-of-principle that targeting the enzymatic activity of HDAC1 is a promising treatment strategy for autoimmune diseases.

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Section: Impact Of Hdac1 Catalytic Activity Inactivation On Gene Expr...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Targeting the catalytic activity of HDAC1 in T cells protects against experimental autoimmune encephalomyelitis

Zhu

Stolz

Simonovic

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, during the cell adhesion cascade fewer histone deacetylase 1 deficient T-cells were found to probe the surface for places to transmigrate. Abolished histone deacetylation further resulted in downregulation of CD11a, CD18 and b7 chain as well as selectins on a transcriptional level, however, deficient T-cells spread more on ICAM-1 and formed more Factin, while their random cell migration speed was increased by 10% (180). It is clear, that as with RhoGTPases, the mechanism of how epigenetic marks regulate leukocyte migration is complex and context dependent and much effort is required to unravel this mechanism fully.…”

Section: B2-integrins Regulate Nuclear Elements and Gene Expression I...mentioning

confidence: 99%

β2-Integrins – Regulatory and Executive Bridges in the Signaling Network Controlling Leukocyte Trafficking and Migration

Guenther

2022

Front. Immunol.

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Leukocyte trafficking is an essential process of immunity, occurring as leukocytes travel within the bloodstream and as leukocyte migration within tissues. While it is now established that leukocytes can utilize the mesenchymal migration mode or amoeboid migration mode, differences in the migratory behavior of leukocyte subclasses and how these are realized on a molecular level in each subclass is not fully understood. To outline these differences, first migration modes and their dependence on parameters of the extracellular environments will be explained, as well as the intracellular molecular machinery that powers migration in general. Extracellular parameters are detected by adhesion receptors such as integrins. β2-integrins are surface receptors exclusively expressed on leukocytes and are essential for leukocytes exiting the bloodstream, as well as in mesenchymal migration modes, however, integrins are dispensable for the amoeboid migration mode. Additionally, the balance of different RhoGTPases – which are downstream of surface receptor signaling, including integrins – mediate formation of membrane structures as well as actin dynamics. Individual leukocyte subpopulations have been shown to express distinct RhoGTPase profiles along with their differences in migration behavior, which will be outlined. Emerging aspects of leukocyte migration include signal transduction from integrins via actin to the nucleus that regulates DNA status, gene expression profiles and ultimately leukocyte migratory phenotypes, as well as altered leukocyte migration in tumors, which will be touched upon.

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“…Particularly, Th2 cytokine interleukin 4 (IL-4) plays a key role in the pathogenesis of allergic disorders (46). HDAC1 can be recruited to the IL-4 gene locus in CD4(+) T cells, thereby promoting the immunoactivity of CD4 positive T cells to increase Th2 cytokine levels (47)(48)(49). The IL-4-induced rat nasal epithelial barrier dysfunction is blocked by HDAC1 inhibitor (Trichostatin A), or sodium butyrate (NaB), or administration of Clostridium Butyricum (Table 1) (14, 62).…”

Section: Regulation Of Inflammatory Cytokines and Downstream Protein ...mentioning

confidence: 99%

The emerging role of histone deacetylase 1 in allergic diseases

Wang

2022

Front. Immunol.

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Histone deacetylase 1 (HDAC1) is a unique member of the classes I HDACs and helps to regulate acute and chronic adaptation to environmental stimuli such as allergen, stress. Allergic diseases are complex diseases resulting from the effect of multiple genetic and interacting foreign substances. Epigenetics play an important role in both pathological and immunomodulatory conditions of allergic diseases. To be consistent with this role, recent evidence strongly suggests that histone deacetylase 1 (HDAC1) plays a critical role in allergic response. HDAC1 expression is stimulated by allergen and attributes to increase T helper 2 (Th2) cytokine levels, decrease Th1/Th17 cells and anti-inflammatory cytokine Interleukin-10 (IL-10), and TWIK-related potassium channel-1 (Trek-1) expression. This review focuses on the contribution of HDAC1 and the regulatory role in characterizing allergic endotypes with common molecular pathways and understanding allergic multimorbidity relationships, as well as addressing their potential as therapeutic targets for these conditions.

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Histone deacetylase 1 controls CD4+ T cell trafficking in autoinflammatory diseases

Cited by 8 publications

References 68 publications

Targeting the catalytic activity of HDAC1 in T cells protects against experimental autoimmune encephalomyelitis

Targeting the catalytic activity of HDAC1 in T cells protects against experimental autoimmune encephalomyelitis

β2-Integrins – Regulatory and Executive Bridges in the Signaling Network Controlling Leukocyte Trafficking and Migration

The emerging role of histone deacetylase 1 in allergic diseases

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