Alarmins: awaiting a clinical response

Chan, James; Roth, Johannes; Oppenheim, Joost J.; Tracey, Kevin J.; Vogl, Thomas; Feldmann, Marc; Horwood, Nicole J.; Nanchahal, Jagdeep

doi:10.1172/jci62423

Cited by 424 publications

(338 citation statements)

References 146 publications

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“…HMGB1 released from damaged or dying cells stimulates innate immunity in neighboring cells (34,35). The inflammatory reactions are thought to prevent initial damage that has caused cell death from spreading to adjacent tissue.…”

Section: Discussionmentioning

confidence: 99%

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

Choi

Cui

Chowdhury

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Maintenance of white matter integrity in health and disease is critical for a variety of neural functions. Ischemic stroke in the white matter frequently results in degeneration of oligodendrocytes (OLs) and myelin. Previously, we found that toll-like receptor 2 (TLR2) expressed in OLs provides cell-autonomous protective effects on ischemic OL death and demyelination in white matter stroke. Here, we identified high-mobility group box-1 (HMGB1) as an endogenous TLR2 ligand that promotes survival of OLs under ischemic stress. HMGB1 rapidly accumulated in the culture medium of OLs exposed to oxygen-glucose deprivation (OGD). This conditioned medium exhibited a protective activity against ischemic OL death that was completely abolished by immunodepletion of HMGB1. Knockdown of HMGB1 or application of glycyrrhizin, a specific HMGB1 inhibitor, aggravated OGD-induced OL death, and recombinant HMGB1 application reduced the extent of OL death in a TLR2-dependent manner. We confirmed that cytosolic translocation of HMGB1 and activation of TLR2-mediated signaling pathways occurred in a focal white matter stroke model induced by endothelin-1 injection. Animals with glycyrrhizin coinjection showed an expansion of the demyelinating lesion in a TLR2-dependent manner, accompanied by aggravation of sensorimotor behavioral deficits. These results indicate that HMGB1/ TLR2 activates an autocrine trophic signaling pathways in OLs and myelin to maintain structural and functional integrity of the white matter under ischemic conditions. white matter stroke | oligodendrocyte | toll-like receptor 2 | HMGB1 | myelination W hite matter in the vertebrate brain is characterized by the presence of myelinated axonal fibers and glial cells, predominantly myelin-producing oligodendrocytes (OLs) (1). The myelin sheath enables rapid communication of neural signals at a millisecond timescale between different parts of the cerebral cortex or different regions of the CNS (2). Therefore, maintaining the integrity of white matter in health and disease, especially of OLs and the myelin sheath, is critical to the performance of a variety of brain functions. Furthermore, recent studies have shown that myelination and OL generation in adulthood are actively regulated in response to neural activities (3, 4), highlighting the potential contribution of white matter plasticity to learning and higher cognitive functions.Ischemic stroke that occurs in the white matter often results in degeneration of OLs and demyelination (5, 6). Consequently, patients with white matter stroke suffer from a wide range of neurological dysfunctions. For example, focal ischemic stroke in the internal capsule may result in severe hemiparesis (7). Furthermore, both cognitive deficits and gait disturbance are hallmarks of Binswanger's subcortical vascular dementia that is the most severe form of white matter stroke (8). How ischemia leads to OL degeneration and demyelination is poorly understood. We previously reported that toll-like receptor 2 (TLR2) expressed in OLs plays a protect...

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Section: Discussionmentioning

confidence: 99%

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

Choi

Cui

Chowdhury

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…6 Therefore, cells constitutively expressing IL-1a were considered "a loaded gun" that can at any time release a proinflammatory alarmin upon cell necrosis. [6][7][8] This way necrotic cells alert surrounding tissues and set up local tissue inflammation.…”

Section: Update On Il-1 Biologymentioning

confidence: 99%

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

Anders

2016

JASN

193

139

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Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic inflammation. In immune cells, inflammasome activation causes the release of mature IL-1b and of the alarmin IL-1a. Dying cells release IL-1a also, independently of the inflammasome. Both IL-1a and IL-1b ligate the same IL-1 receptor (IL-1R) that is present on nearly all cells inside and outside the kidney, further amplifying cytokine and chemokine release. Thus, the inflammasome-IL-1a/IL-b-IL-1R system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflammation. This review gives an overview of arising concepts of inflammasome and IL-1a/b regulation in renal cells and in experimental kidney disease models. There is a pipeline of compounds that can interfere with the inflammasome-IL-1a/IL-b-IL-1R system, ranging from recently described small molecule inhibitors of NLRP3, a component of the inflammasome complex, to regulatory agency-approved IL-1-neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the potential therapeutic benefits of using such compounds to block the inflammasome-IL-1a/IL-b-IL-1R system in kidney disease should be further explored.

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“…Although S100A8 and S100A9 are able to form homodimers, they typically exhibit pro-and anti-inflammatory properties (2) by forming heterodimers of S100A8/A9, alternatively known as calprotectin (3,4). High serum levels of S100A8/A9 correlate with inflammatory response in a number of chronic diseases, including rheumatic arthritis, inflammatory bowel disease and atherosclerosis (5). S100A8/A9 is proposed to be a sensitive biomarker for monitoring inflammatory activities (6).…”

Section: Introductionmentioning

confidence: 99%

S100A8/A9 is associated with estrogen receptor loss in breast cancer

Bao

Wang

2016

Oncology Letters

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Abstract. S100A8 and S100A9 are calcium-binding proteins that are secreted primarily by granulocytes and monocytes, and are upregulated during the inflammatory response. S100A8 and S100A9 have been identified to be expressed by epithelial cells involved in malignancy. In the present study, the transcriptional levels of S100A8 and S100A9 were investigated in various subtypes of breast cancer (BC), and the correlation with estrogen receptor 1 (ESR1) and GATA binding protein 3 (GATA3) gene expression was evaluated using microarray datasets. The expression of S100A8 and S100A9 in BC cells was assessed by reverse transcription-polymerase chain reaction (RT-PCR). The regulation of ESR1 and GATA3 by administration of recombinant S100A8/A9 was examined in the BC MCF-7 cell line using quantitative (q)PCR. The association between S100A8 and S100A9 and overall survival (OS) was investigated in GeneChip ® data of BC. The expression levels of S100A8 and S100A9 were higher in human epidermal growth factor receptor 2 (Her2)-amplified and basal-like BC. The messenger (m)RNA levels of S100A8 and S100A9 were inversely correlated with ESR1 and GATA3 expression. S100A8/A9 induced a 10-fold decrease in the mRNA levels of ESR1 in MCF-7 cells. Poor OS was associated with high expression levels of S100A9, but not with high expression levels of S100A8 in BC. In conclusion, strong expression and secretion of S100A8/A9 may be associated with the loss of estrogen receptor in BC, and may be involved in the poor prognosis of Her2 + /basal-like subtypes of BC.

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Alarmins: awaiting a clinical response

Cited by 424 publications

References 146 publications

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

High-mobility group box-1 as an autocrine trophic factor in white matter stroke

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

S100A8/A9 is associated with estrogen receptor loss in breast cancer

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