The loop that feeds itself
IL-1beta and TNF act on nearby cells and on the endothelium. Endothelial activation recruits more leukocytes, which release reactive oxygen species and proteases. Those proteases damage neighboring cells and generate more DAMPs. The new DAMPs prime and activate more inflammasomes, which release more IL-1beta. NF-kB is activated at every step, so the transcriptional program that produces the cytokines is continuously re-primed. Nothing in this cycle requires the original stressor to persist.
Senescent cells as a fixed source
A senescent cell is the clearest example of a source that does not resolve on its own. It cannot be cleared by the cell cycle, and it survives for long periods while secreting the SASP. Because the SASP includes IL-1beta and IL-6, it sustains NF-kB in the surrounding tissue and can induce senescence in neighboring cells, expanding the source. This is why senescent cell burden correlates with age-related inflammatory disease rather than resolving after the initial damage.
The duration rule established for the ER, mitochondrial, and metabolic programs applies here at the tissue level: a response that is protective when brief becomes pathological when it is sustained, because the response itself generates the signal that maintains it.
Applying the rule
Consider a tissue with a small population of senescent cells after an episode of oxidative damage. If the senescent cells are cleared, IL-1beta and IL-6 fall, NF-kB activity drops in the surrounding tissue, and the inflammation resolves. If they persist, the SASP keeps NF-kB active, recruits immune cells that release more reactive oxygen species, and generates new senescent cells. The prediction is not that the original damage recurs, but that the inflammatory state becomes independent of it. The same logic applies to a chronic metabolic stress: sustained lipid overload keeps mitochondrial ROS high, which keeps the inflammasome primed, which keeps IL-1beta in the tissue.