Researchers at the University of California, Los Angeles have identified a mechanism by which macrophages, a type of immune cell, retain memories of past infections. Their findings will be published in the Journal of Experimental Medicine on February 18. The study focuses on how lingering signaling molecules from previous infections help keep these cells ready to respond more effectively if similar threats reappear.
Macrophages are responsible for detecting and destroying invading microbes or abnormal cells within body tissues. They also signal other immune cells to contribute to inflammation or tissue repair. Recent research has shown that macrophages can "remember" earlier encounters, allowing them to react more strongly during subsequent exposures.
The UCLA team found that this memory relies on a cytokine called interferon gamma. When macrophages first encounter an infection, interferon gamma causes certain DNA regions in these cells to open up, forming "enhancer" domains that prime hundreds of genes involved in immune responses for rapid activation if needed again. However, it was unclear how this memory is maintained over time after the initial exposure.
According to lead author Aleksandr Gorin, who is both an infectious disease physician and postdoctoral researcher in the Hoffmann laboratory, human macrophages briefly exposed to interferon gamma create thousands of new enhancers that persist for days and improve their response to bacterial signals. The researchers discovered that small amounts of interferon gamma remain attached to macrophages and their immediate environment even after most of it has been cleared away.
Further experiments showed that continued signaling from this residual interferon gamma is necessary for maintaining the macrophage's memory. When Gorin blocked these persistent signals, the enhancer regions were erased and the macrophage response weakened.
"We suggest that acute immune activity within a tissue in response to infection or injury may 'stain' the tissue with cytokines and that ongoing signaling from these molecules contributes to lasting changes in tissue resident macrophages," Gorin said. Hoffmann added: "Our observation that the interferon gamma–induced memory state is pharmacologically reversible raises the possibility that at least some trained immune states can be pharmacologically erased or modified by blocking cytokine signaling pathways."
This approach could have therapeutic implications for autoimmune diseases such as lupus or rheumatoid arthritis, where misprogrammed macrophages attack healthy tissues. Erasing maladaptive immune memories might help reduce harmful inflammation in these conditions.
