A report in Nature describes a fail-safe mechanism in apoptotic cells that avoids inflammation after secondary necrosis, in which apoptotic cells change the structure of their chromatin.
Apoptotic cells are tidy — they organize their funeral while they are dying, so cellular remnants are promptly removed without any spillage of intracellular content or collateral damage. By contrast, necrotic cells become leaky, and this causes damage to neighbouring cells and inflammation. When apoptotic cells escape clearance, however, they undergo secondary necrosis. A report in Nature now describes a fail-safe mechanism in apoptotic cells that avoids inflammation after secondary necrosis, in which apoptotic cells change the structure of their chromatin, which allows it to trap a pro-inflammatory protein called high mobility group protein-1 (HMGB1).
HMGB1 functions as an architectural DNA-binding factor that is involved in nucleoprotein complex assembly. It also acts as a mediator of inflammation when it is secreted by activated monocytes and macrophages. Marco Bianchi and colleagues now show that these two functions are linked.
The authors first observed that HMGB1 leaks out of necrotic, but not apoptotic, cells. HMGB1 was indeed found to be tightly associated with the chromatin of apoptotic cells, even when their membrane is permeabilized artificially with detergents. As nucleosomal fragmentation is one of the hallmarks of apoptosis, the authors next tested whether DNA fragmentation is responsible for the affinity of HMGB1 for chromatin in apoptotic cells. But inhibition of DNA fragmentation did not block HMGB1 binding. Acetylation also affects chromatin structure, so they tested whether treatment with a deacetylase inhibitor before the induction of apoptosis would suppress HMGB1 binding to chromatin — and it did. This indicates that chromatin hypoacetylation occurs during apoptosis, and allows HMGB1 binding. Consistent with this histone H4 was found to be hypoacetylated in apoptotic cells.
What does HMGB1 binding to chromatin do in apoptosis? Hmgb1-deficient cells are as sensitive as wild-type cells to apoptosis, which indicates that HMGB1 is not required for apoptosis. So, could HMGB1 binding to chromatin avoid its leakage and the subsequent inflammation? To test this, Bianchi and colleagues incubated bone-marrow cells with wild-type or Hmgb1-deficient dead fibroblasts. The Hmgb1-deficient necrotic cells were much less efficient than wild-type necrotic cells at eliciting the production of tumour-necrosis factor- (TNF-) by monocytes. Remnants from cells that had been induced to undergo secondary necrosis after prolonged exposure to an apoptotic stimulus also failed to induce any inflammation. However, remnants from fibroblasts that were treated with both TNF- and a deacetylase inhibitor triggered inflammation as potently as wild-type necrotic cells.
The role of HMGB1 in inflammation after tissue necrosis was confirmed in vivo
— mice that were exposed to an overdose of paracetamol undergo massive liver necrosis and subsequent inflammation. And, although anti-HMGB1 antibodies did not block liver damage, they reduced inflammation considerably. So, by changing the structure of their chromatin and tethering the pro-inflammatory protein HMGB1, apoptotic cells altruistically die in silence and spare their neighbours.
Valerie Ferrier
References
Scaffidi, P. , Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature418, 191 – 195 (2002) | Article | PubMed |
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