Key Role of DAMP in Inflammation, Cancer, and Tissue Repair

Pandolfi, Franco; Altamura, Simona; Frosali, Simona; Conti, Pio

doi:10.1016/j.clinthera.2016.02.028

Cited by 136 publications

(87 citation statements)

References 139 publications

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“…In addition to their proinflammatory roles, recent studies have linked DAMPs to noninflammatory functions such as promoting cellular migration and proliferation, angiogenesis, and tissue repair (33,40). In particular, HMGB1 was shown to contribute to spinal cord regeneration in animal models where spontaneous regeneration occurs (41,42).…”

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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“…More importantly, our siRNA knockdown studies resulted in significant effects on HMGB1 related vasculogenic/angiogenic functions. High-mobility group box-1 (HMGB1) protein is a transcription factor that has a dual role as a mobile chromatin protein and as a cytokine49. Amongst its functions, HMGB1 has been implicated in tissue repair and regeneration by promoting chemotaxis of stem/progenitor cells, stimulating the proliferation of tissue resident stem/progenitor cells including endothelial cells and vascular smooth muscle cells, acting as a proangiogenic cytokine and promoting secretion of proangiogenic cytokines such as VEGF and CXCL85051525354.…”

Section: Discussionmentioning

confidence: 99%

miR-193a-3p interaction with HMGB1 downregulates human endothelial cell proliferation and migration

Khoo

Roubelakis

Schrader

et al. 2017

Sci Rep

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Circulating endothelial colony forming cells (ECFCs) contribute to vascular repair where they are a target for therapy. Since ECFC proliferative potential is increased in cord versus peripheral blood and to define regulatory factors controlling this proliferation, we compared the miRNA profiles of cord blood and peripheral blood ECFC-derived cells. Of the top 25 differentially regulated miRNAs selected, 22 were more highly expressed in peripheral blood ECFC-derived cells. After validating candidate miRNAs by q-RT-PCR, we selected miR-193a-3p for further investigation. The miR-193a-3p mimic reduced cord blood ECFC-derived cell proliferation, migration and vascular tubule formation, while the miR-193a-3p inhibitor significantly enhanced these parameters in peripheral blood ECFC-derived cells. Using in silico miRNA target database analyses combined with proteome arrays and luciferase reporter assays of miR-193a-3p mimic treated cord blood ECFC-derived cells, we identified 2 novel miR-193a-3p targets, the high mobility group box-1 (HMGB1) and the hypoxia upregulated-1 (HYOU1) gene products. HMGB1 silencing in cord blood ECFC-derived cells confirmed its role in regulating vascular function. Thus, we show, for the first time, that miR-193a-3p negatively regulates human ECFC vasculo/angiogenesis and propose that antagonising miR-193a-3p in less proliferative and less angiogenic ECFC-derived cells will enhance their vasculo/angiogenic function.

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“…To further find conclusive evidence regarding the regulation of HMGB1 in pro-inflammatory function after chemotherapy, ATRA-induced NB4 cells that were incubated with 10 μg/ml neutralizing antibody against HMGB1 [20] showed partial reduction of TNF-α and IL-1β secretion compared to the negative control (Figure 7A). In addition, treatment of HMGB1-neutralizing antibody partially inhibited ICAM-1 elevation (Figure 7B) and reduced ERK1/2 phosphorylation compared to the ATRA-treated group (Figure 7C).…”

Section: Resultsmentioning

confidence: 99%

“…Emigration of ATRA-treated APL cells into lungs and other tissues recapitulates the molecular events during inflammation and immune responses [21]. The major molecular mediators of inflammation during ATRA-induced APL are pro-inflammatory cytokines and ICAM-1 [20, 22]. ATRA induces release of early pro-inflammatory cytokines such as TNF-α and IL-1β [22, 23], which promote endothelial adhesion in NB4 cells [24, 25].…”

Section: Discussionmentioning

confidence: 99%

HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells

Tang

Chai

et al. 2017

Oncotarget

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Differentiation therapy based on all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) for the treatment of acute promyelocytic leukemia (APL) is complicated by the development of differentiation syndrome (DS), which can be fatal. We examined the role of HMGB1 (high-mobility group box 1) in DS using both in vitro and in vivo models. HMGB1 and the pro-inflammatory cytokines IL-1β and TNF-α were gradually released from NB4 and HL-60 cells treated with ATRA and/or ATO. Similarly, higher serum HMGB1 levels positively correlated with the clinical status of DS patients. Exogenous HMGB1 promoted rapid release of IL-1β and TNF-α as well as elevated expression of ICAM-1, without altering cell differentiation. Exogenous HMGB1 also enhanced pulmonary infiltration and up-regulated ICAM-1 expression in the ATRA-treated DS mouse. Pharmacological inhibition or depletion of MEK1/2 reduced the cytokine levels and suppressed expression of ICAM-1 and the adhesion of HMGB1-treated NB4 cells to endothelial cells, implicating MEK/ERK signaling in the response to HMGB1 during DS. Treatment with a HMGB1-neutralizing antibody reduced secretion of TNF-α and IL-1β, arrested the elevation of ICAM-1 and blunted the activation of ERK1/2 in ATRA-induced NB4 cells. The HMGB1-neutralizing antibody also decreased ICAM-1 expression and reduced mortality in ATRA-treated DS model mice. These findings demonstrate that released HMGB1 is central to DS, and that targeting HMGB1 may be of therapeutic value in the treatment of DS.

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Key Role of DAMP in Inflammation, Cancer, and Tissue Repair

Abstract: Due to the bivalent nature of DAMP, it is often difficult to explain the relative role of DAMP in inflammation versus its role in tissue repair. However, this point is crucial as DAMP-related treatments move into clinical practice.

Cited by 136 publications

References 139 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

miR-193a-3p interaction with HMGB1 downregulates human endothelial cell proliferation and migration

HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells

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