Now, researchers at Osaka University have identified a new player that activates macrophages and allows them to take on a protective role against inflammatory disorders such as sepsis and inflammatory bowel disease (IBD).

Macrophages are white blood cells that perform different functions with different energy needs. M2-type macrophages have anti-inflammatory properties that may protect against inflammatory disorders such as inflammatory bowel disease (IBD).

However, the molecular pathways driving M2 formation are not fully understood. Researchers identified a protein commonly involved in nervous system development that plays a key role in the metabolism of M2 macrophages and protecting against colitis symptoms in mice. The findings may lead to new therapeutic targets for inflammatory diseases.

Activated macrophages are traditionally classified as either pro- (M1) or anti- (M2) inflammatory macrophages. The M1 type is part of the inflammatory response that kills invading organisms.

M2-type macrophages, by contrast, have anti-inflammatory properties and are thought to protect against inflammatory disorders such as sepsis and IBD. The researchers were interested in understanding precisely what drives macrophages to form the M2 type.

"M1 and M2 macrophages have different energy needs, so macrophages need to be able to sense and respond to nutrients in their surroundings as part of the activation process," study lead author Sujin Kang explains.

"We already knew that macrophages altered their metabolism when they differentiated to the M2 subtype, but we didn't understand exactly how this metabolic reprogramming worked," said Kang.

To gain insight into how M2 macrophages meet their energy demands, the researchers focused on a signaling pathway called mTOR, which is involved in cell metabolism and known to drive macrophages to the M2 type.

They used a chemical inhibitor to shut down the activity of the mTOR protein, allowing them to see how other players in the pathway were affected. "Once we found we could block M2 differentiation, we wanted to see how this impacted the protective role of macrophages in chronic inflammatory diseases," Kang added.

"Using a model that mimics colitis, we found that mice lacking Sema6D have much more severe symptoms. Sema6D-deficient mice have significantly less body weight, a shorter colon, severe infiltration of inflammatory cells, and extensive damage to the cells lining the colon," Kang said.

The findings have potentially important clinical implications, as they provide a new potential therapeutic target for the treatment of inflammatory diseases such as IBD. "Our study demonstrates a key role for Sema6D in the metabolic reprogramming that occurs during the formation of M2 macrophages," lead investigator Atsushi Kumanogoh concluded.

"Our findings suggest that Sema6D dysfunction prevents macrophages from differentiating to the anti-inflammatory M2 type, leaving the body more vulnerable to inflammatory pathologies. We're hopeful that this discovery offers new leads in the drug discovery process for these diseases," Kumanogoh added.