Cutting Edge: Critical Role for Mesothelial Cells in Necrosis-Induced Inflammation through the Recognition of IL-1α Released from Dying Cells

Eigenbrod, Tatjana; Park, Jong Hwan; Harder, Jürgen; Iwakura, Yoichiro; Núñez, Gabriel

doi:10.4049/jimmunol.181.12.8194

Cited by 213 publications

(208 citation statements)

References 26 publications

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“…Since IL-1a released from necrotic cells is proinflammatory [4], we propose that intranuclear retention of IL-1a represents a mechanism for attenuating inflammation caused by the death of IL-1a-expressing cells. IL-1a is expressed by healthy cells in some tissues including skin, liver and spleen [25][26][27].…”

Section: Discussionmentioning

confidence: 97%

“…IL-1a is expressed by healthy cells in some tissues including skin, liver and spleen [25][26][27]. IL-1a released from these cells after tissue damage acts as a DAMP activating sterile inflammation [4]. IL-1a expression is also induced in immune cells by DAMP [1], and will be released from immune cells following necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Intranuclear IL-1a is retained by necrotic microglia Since IL-1a release from necrotic cells is pro-inflammatory [4], we hypothesized that IL-1a nuclear localization represents a mechanism to inhibit IL-1a release, and so inhibits inflammation induced by necrotic cells. Thus, the reduced IL-1a nuclear localization in high-density microglia would result in increased IL-1a release after necrosis.…”

Section: Il-1a Nuclear Localization Is Inhibited At High Cell Densitymentioning

confidence: 99%

“…Intracellular molecules released from necrotic cells act as damage-associated molecular patterns (DAMP), signaling to the innate immune system that tissue injury has occurred [2]. IL-1a, a pro-inflammatory member of the IL-1 cytokine family [3], has recently been identified as a DAMP released from necrotic cells [4]. In addition, necrotic cell DAMP are reported to stimulate IL-1a production by immune cells, which further exacerbates sterile inflammation [1].…”

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Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

2009

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Sterile inflammation is a host response to tissue injury that is mediated by damage-associated molecular patterns released from dead cells. Sterile inflammation worsens damage in a number of injury paradigms. The pro-inflammatory cytokine IL-1a is reported to be a damage-associated molecular pattern released from dead cells, and it is known to exacerbate brain injury caused by stroke. In the brain, IL-1a is produced by microglia, the resident brain macrophages. We found that IL-1a is actively trafficked to the nuclei of microglia, and hence tested the hypothesis that trafficking of IL-1a to the nucleus would inhibit its release following necrotic cell death, limiting sterile inflammation. Microglia subjected to oxygenglucose deprivation died via necrosis. Under these conditions, microglia expressing nuclear IL-1a released significantly less IL-1a than microglia with predominantly cytosolic IL-1a. The remaining IL-1a was immobilized in the nuclei of the dead cells. Thus, nuclear retention of IL-1a may serve to limit inflammation following cell death.Key words: IL-1a . Microglia . Necrosis . Nuclear retention . Sterile inflammation Supporting Information available online IntroductionSterile inflammation is a host response to tissue injury that can exacerbate the initial insult [1]. Intracellular molecules released from necrotic cells act as damage-associated molecular patterns (DAMP), signaling to the innate immune system that tissue injury has occurred [2]. IL-1a, a pro-inflammatory member of the IL-1 cytokine family [3], has recently been identified as a DAMP released from necrotic cells [4]. In addition, necrotic cell DAMP are reported to stimulate IL-1a production by immune cells, which further exacerbates sterile inflammation [1]. Experimental stroke in rodents elicits an inflammatory response that markedly exacerbates brain injury [5]. IL-1a is a key contributor to this injury, and its genetic ablation (along with IL-1b, a related cytokine) causes a 70% reduction in the brain injury caused by stroke [6].In the brain after injury (e.g. stroke, hemorrhage, trauma), IL-1 family cytokines are produced by microglia, the resident brain macrophages [7]. IL-1a is produced in the cytosol as a 31-kDa protein that, following release from necrotic cells, activates the type I IL-1 receptor on responsive cell membranes [8,9]. The Nterminal domain of IL-1a contains a nuclear localization sequence, which mediates active nuclear import [10,11]. IL-1a has been reported to act within the nucleus to regulate cytokine transcription and RNA splicing [12,13]. In this study we sought to test the hypothesis that IL-1a nuclear import also inhibits IL-1a release following necrotic cell death. We report that IL-1a nuclear import and intranuclear retention reduce IL-1a release from necrotic microglia. Thus, IL-1a nuclear retention by necrotic cells may inhibit injury-induced inflammation. Results IL-1a nuclear localization is inhibited at high cell densityTo investigate the effects of IL-1a nuclear localization on IL-1a release after ne...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Il-1a Nuclear Localization Is Inhibited At High Cell Densitymentioning

confidence: 99%

mentioning

confidence: 99%

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Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

2009

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“…Because of its nuclear localization sequence, IL-33 is usually present in the nucleus, where it acts as a potential transcriptional repressor [16]. Recently, IL-33 has been shown to be released from necrotic cells and may act as an alarmin in a similar manner to IL-1a [17] or high mobility group box1 protein HMGB1 [18,19]. [14].…”

Section: Introductionmentioning

confidence: 99%

IL‐33‐activated dendritic cells are critical for allergic airway inflammation

et al. 2011

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IL-33, a new member of the IL-1 family cytokine, is involved in Th2-type responses in a wide range of diseases and signals through the ST2 receptor expressed on many immune cells. Since the effects of IL-33 on DCs remain controversial, we investigated the ability of IL-33 to modulate DC functions in vitro and in vivo. Here, we report that IL-33 activates myeloid DCs to produce IL-6, IL-1b, TNF, CCL17 and to express high levels of CD40, CD80 OX40L and CCR7. Importantly, IL-33-activated DCs prime naive lymphocytes to produce the Th2 cytokines IL-5 and IL-13, but not IL-4. In vivo, IL-33 exposure induces DC recruitment and activation in the lung. Using an OVA-induced allergic lung inflammation model, we demonstrate that the reduced airway inflammation in ST2-deficient mice correlates with the failure in DC activation and migration to the draining LN. Finally, we show that adoptive transfer of IL-33-activated DCs exacerbates lung inflammation in a DC-driven model of allergic airway inflammation. These data demonstrate for the first time that IL-33 activates DCs during antigen presentation and thereby drives a Th2-type response in allergic lung inflammation. IntroductionAllergic asthma is a chronic disorder characterized by eosinophilic airway inflammation, mucus hypersecretion, antigenspecific-IgE antibodies, airway remodeling and increased airway hyperreactivity [1,2]. The process of airway inflammation involves various cells types, such as eosinophils, mast cells, epithelial cells, lymphocytes and DCs. Th2 cells have been shown to play a predominant role in allergic asthma and Th2 cytokines, such as IL-4, IL-5 and IL-13, exacerbate disease severity [3,4]. IL-33, the recently discovered Th2 cytokine, is found at high levels in the plasma of asthmatic patients [5,6] and in the lungs of mice during experimental allergic asthma [7,8].IL-33 is a member of IL-1 family [9][10][11]. Like IL-1b or IL-18, IL-33 is synthesized as a precursor and can be cleaved by caspase-1 and 3 but the cleavage products are biologically less active than the precursor [12,13]. In contrast to the other IL-1 family members, IL-33 is mainly expressed in non-hematopoietic cells such as fibroblasts, epithelial cells and endothelial cells [10,14,15]. Because of its nuclear localization sequence, IL-33 is usually present in the nucleus, where it acts as a potential transcriptional repressor [16]. Recently, IL-33 has been shown to be released from necrotic cells and may act as an alarmin in a similar manner to IL-1a [17] or high mobility group box1 protein HMGB1 [18,19]. [14]. In accordance with its Th2 functions, administration of IL-33 into naive mice induces severe inflammation in the lung and digestive tract with elevated levels of IL-4, IL-5 and IL-13, splenomegaly and increased serum Ig [10]. In vitro, IL-33 has also been reported to polarize naive CD4 1 T cells to produce IL-5 and IL-13, but not . Polarization of this atypical Th2 population is independent of IL-4, STAT6 and GATA3. On macrophages, IL-33 amplifies IL-13-mediated polarization...

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Damage-associated Molecular Patterns

Cavaillon

2017

Inflammation - From Molecular and Cellular Mechanisms to the Clinic

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Cutting Edge: Critical Role for Mesothelial Cells in Necrosis-Induced Inflammation through the Recognition of IL-1α Released from Dying Cells

Cited by 213 publications

References 26 publications

Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

IL‐33‐activated dendritic cells are critical for allergic airway inflammation

Damage-associated Molecular Patterns

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