Lingering Immune Signals Fuel Macrophage Memory

Macrophages are some of the body’s most potent weapons against invading cellular threats. Like immunological ‘Hungry Hungry Hippos,’ macrophages engulf and dispose of cancer cells or invasive pathogens. They can also send signals to other immune cells to pile in to the fight, ramping up the response.

While immune memory has traditionally been associated with adaptive cells like lymphocytes, which can recognize specific antigens during a reinfection, emerging studies indicate that macrophages also have memory-like function. Research has shown that the cells recognize threats they have previously encountered and fire up a stronger reaction upon a second meeting.¹

A new study, published in the Journal of Experimental Medicine, has made strides toward understanding how these cells maintain this memory, by showing that tiny immune signaling molecules stick around on macrophages to keep them in a state of readiness.² The findings could help reduce the impact of autoimmune diseases like arthritis, where the immune system remembers the wrong threats and attacks the body.

Interferon Gamma Gets Macrophages Pumped Up

Recent studies of macrophages have shown that their memories rely on a cytokine signaling molecule called interferon gamma (IFNγ).³ When the immune system encounters a threat for the first time, IFNγ induces changes in macrophages’ DNA, exposing enhancer domains that pump up gene expression. The newly bolstered genes explain how the immune system can respond faster and more forcefully when it next encounters the threat. But researchers didn’t fully understand how the macrophages maintained this memory for so long after their exposure to IFNγ.

“Our new findings suggest that these changes in macrophages are actually readily reversible and do not inherently encode immune memory,” said University of California, Los Angeles (UCLA) microbiologist and study co-author Alexander Hoffmann in a statement. “Instead, the cells are dependent on ongoing signaling from interferon gamma sequestered at or near the macrophage cell surface.”

For their study, the researchers exposed cultured macrophages to IFNγ and then studied epigenetic changes in the cells’ genomes. They recorded thousands of shifts in immune-boosting enhancers that lasted for days after exposure. These shifts were only sustained because of continued signaling from minuscule amounts of IFNγ that remained attached to the macrophages.

Calming Macrophages Could Help Treat Autoimmunity

When Hoffmann, alongside UCLA infectious disease physician and study lead researcher Aleksandr Gorin, blocked signals from these residual cytokine molecules, the macrophages’ enhancers calmed and reduced their response to bacterial threats.

“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,” said Gorin.

If this possibility is confirmed in further studies, it could have important consequences for the study of diseases in which misdirected immune responses cause damage, the authors noted.

“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,” said Hoffmann.