Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery

Ito, Minako; Komai, Kyoko; Mise-Omata, Setsuko; Iizuka‐Koga, Mana; Noguchi, Yoshiko; Kondo, Taisuke; Sakai, Ryota; Matsuo, Keitaro; Nakayama, Takashi; Yoshie, Osamu; Nakatsukasa, Hiroko; Chikuma, Shunsuke; Shichita, Takashi; Yoshimura, Akihiko

doi:10.1038/s41586-018-0824-5

Cited by 495 publications

(583 citation statements)

References 38 publications

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“…These findings clearly demonstrated that endogenous expression of Amphiregulin is essential to ensure efficient T reg function. In line with this immune‐suppressive function of Amphiregulin, it has been reported that also following ischaemic stroke T reg ‐derived Amphiregulin contributes to neurological recovery by suppressing IL‐6 expression within the brain and thus avoiding neurotoxic astrogliosis …”

Section: The Role Of Amphiregulin In Immune Regulation and Wound Healmentioning

confidence: 79%

“…In particular, FoxP3‐expressing regulatory CD4 T‐cells (T regs ) appear to play a critical role in this transition. T regs rapidly migrate to and accumulate at sites of inflammation, such as at sites of injury . Depletion of T regs during the different phases of wound healing, for instance by the application of diphtheria toxin (DT) to FoxP3:DTR transgenic mice or by the injection of CD25‐depleting antibodies, consistently led to aggravated inflammation and deteriorated clinical outcomes in a number of different injury model systems in mice …”

Section: Regulatory T‐cells Have An Established Role In Wound Healingmentioning

confidence: 99%

“…Amphiregulin‐expressing T regs are typically restricted to tissue‐resident T reg populations and thus suggest an organ‐specific role for T reg ‐expressed Amphiregulin . These tissue‐resident T reg populations also preferentially express the IL‐33 receptor, T1/ST2 . The role of T1/ST2 expression on T regs currently remains unresolved.…”

Section: The Function Of Regulatory T‐cell‐derived Amphiregulinmentioning

confidence: 99%

“…Such a poised state of tissue‐resident T reg populations could be critical during tissue injury, for instance due to the fact that IL‐33 release from necrotic cells is a very early event during tissue injury in many tissues. Thus, this poised state may allow to already induce the activation and expansion of T reg populations at the site of injury, while the infiltration of T reg populations derived from secondary lymphoid organs into injured tissues may so far not have been initiated yet . Thus, the constitutive expression of Amphiregulin by tissue‐resident T regs may constitute a first line of defence during wounding.…”

Section: The Function Of Regulatory T‐cell‐derived Amphiregulinmentioning

confidence: 99%

“…[4][5][6] Depletion of T regs during the different phases of wound healing, for instance by the application of diphtheria toxin (DT) to FoxP3:DTR transgenic mice or by the injection of CD25depleting antibodies, consistently led to aggravated inflammation and deteriorated clinical outcomes in a number of different injury model systems in mice. 4,[6][7][8][9][10][11][12] For instance, in mouse models of myocardic infarction, the depletion of T regs resulted in aggravated cardiac inflammation and deteriorated clinical outcome. 9,10 In these experiments, T reg cell depletion was associated with increased neutrophil and monocyte infiltration, and diminished alternatively activated macrophage polarization.…”

Section: Regulatory T-cells Have An Established Role In Wound Healingmentioning

confidence: 99%

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Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

2019

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Summary The immune system has a well‐established contribution to tissue homeostasis and wound healing. However, in many cases immune responses themselves can cause severe tissue damage. Thus, the question arose to which extent cells of the immune system directly contribute to the process of wound healing and to which extent the resolution of excessive immune responses may indirectly contribute to wound healing. FoxP3‐expressing CD4 T‐cells, so‐called regulatory T‐cells (Tregs), have an important contribution in the regulation of immune responses; and, in recent years, it has been suggested that Tregs next to an immune‐regulatory, ‘damage‐limiting’ function may also have an immune‐independent ‘damage‐resolving’ direct role in wound healing. In particular, the release of the epidermal growth factor‐like growth factor Amphiregulin by tissue‐resident Tregs during wound repair suggested such a function. Our recent findings have now revealed that Amphiregulin induces the local release of bio‐active transforming growth factor (TGF)β, a cytokine involved both in immune regulation as well as in the process of wound repair. In light of these findings, we discuss whether, by locally activating TGFβ, Treg‐derived Amphiregulin may contribute to both wound repair and immune suppression. Furthermore, we propose that Treg‐derived Amphiregulin in an autocrine way may enable an IL‐33‐mediated survival and expansion of tissue‐resident Tregs upon injury. Furthermore, Treg‐derived Amphiregulin may contribute to a constitutive, low‐level release of bio‐active TGFβ within tissues, leading to continuous tissue regeneration and to an immune‐suppressive environment, which may keep inflammation‐prone tissues in an homeostatic state.

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Section: The Role Of Amphiregulin In Immune Regulation and Wound Healmentioning

confidence: 79%

Section: Regulatory T‐cells Have An Established Role In Wound Healingmentioning

confidence: 99%

Section: The Function Of Regulatory T‐cell‐derived Amphiregulinmentioning

confidence: 99%

Section: The Function Of Regulatory T‐cell‐derived Amphiregulinmentioning

confidence: 99%

Section: Regulatory T-cells Have An Established Role In Wound Healingmentioning

confidence: 99%

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Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

2019

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Medical Applications of Porous Biomaterials: Features of Porosity and Tissue‐Specific Implications for Biocompatibility

Hernandez

Woodrow

2022

Adv Healthcare Materials

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Porosity is an important material feature commonly employed in implants and tissue scaffolds. The presence of material voids permits the infiltration of cells, mechanical compliance, and outward diffusion of pharmaceutical agents. Various studies have confirmed that porosity indeed promotes favorable tissue responses, including minimal fibrous encapsulation during the foreign body reaction (FBR). However, increased biofilm formation and calcification is also described to arise due to biomaterial porosity. Additionally, the relevance of host responses like the FBR, infection, calcification, and thrombosis are dependent on tissue location and specific tissue microenvironment. In this review, the features of porous materials and the implications of porosity in the context of medical devices is discussed. Common methods to create porous materials are also discussed, as well as the parameters that are used to tune pore features. Responses toward porous biomaterials are also reviewed, including the various stages of the FBR, hemocompatibility, biofilm formation, and calcification. Finally, these host responses are considered in tissue specific locations including the subcutis, bone, cardiovascular system, brain, eye, and female reproductive tract. The effects of porosity across the various tissues of the body is highlighted and the need to consider the tissue context when engineering biomaterials is emphasized.

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A Therapeutic Nanovaccine that Generates Anti‐Amyloid Antibodies and Amyloid‐specific Regulatory T Cells for Alzheimer's Disease

et al. 2022

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Alzheimer's disease (AD), the most common cause of dementia, is a complex condition characterized by multiple pathophysiological mechanisms including amyloid‐β (Aβ) plaque accumulation and neuroinflammation in the brain. The current immunotherapy approaches, such as anti‐Aβ monoclonal antibody (mAb) therapy, Aβ vaccines, and adoptive regulatory T (Treg) cell transfer, target a single pathophysiological mechanism, which may lead to unsatisfactory therapeutic efficacy. Furthermore, Aβ vaccines often induce T helper 1 (Th1) cell‐mediated inflammatory responses. Here, a nanovaccine composed of lipid nanoparticles loaded with Aβ peptides and rapamycin is developed, which targets multiple pathophysiological mechanisms, exhibits the combined effects of anti‐Aβ antibody therapy and adoptive Aβ‐specific Treg cell transfer, and can overcome the limitations of current immunotherapy approaches for AD. The Nanovaccine effectively delivers rapamycin and Aβ peptides to dendritic cells, produces both anti‐Aβ antibodies and Aβ‐specific Treg cells, removes Aβ plaques in the brain, alleviates neuroinflammation, prevents Th1 cell‐mediated excessive immune responses, and inhibits cognitive impairment in mice. The nanovaccine shows higher efficacy in cognitive recovery than an Aβ vaccine. Unlike anti‐Aβ mAb therapy and adoptive Treg cell transfer, both of which require complicated and costly manufacturing processes, the nanovaccine is easy‐to‐prepare and cost‐effective. The nanovaccines can represent a novel treatment option for AD.

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Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery

Cited by 495 publications

References 38 publications

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

Medical Applications of Porous Biomaterials: Features of Porosity and Tissue‐Specific Implications for Biocompatibility

A Therapeutic Nanovaccine that Generates Anti‐Amyloid Antibodies and Amyloid‐specific Regulatory T Cells for Alzheimer's Disease

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