Immune cells not only destroy pathogens but might also cause collateral injuries to normal tissues. The surprisingly low incidence of post-inflammatory complications is explained here by a 'danger-sensing' physiological mechanism that ensures the tissue-protecting negative feedback inhibition of overactive immune cells. We focus here on immunoregulatory influences of 'non-immune' signaling molecules in physiological and pathophysiological tissue microenvironments. We propose that hypoxia-associated accumulation of extracellular adenosine might be an important immunoregulatory signal. A2 receptors for extracellular adenosine might act as both primary sensors of excessive collateral tissue damage during an immune response and triggers of the emergency downregulation of overactive immune cells. Regulation by extracellular adenosine would protect normal organs from injury and/or re-direct immune responses.