Researchers from Osaka University have identified a protein involved in the activation of immune cells that can protect against inflammatory disorders such as sepsis and inflammatory bowel disease.
Credit: Kateryna Kon/Shutterstock.com
The finding is potentially important, since it could lead to the development of new treatments for such conditions.
Immune cells called macrophages are classified as either pro- (M1) or anti- (M2) inflammatory macrophages.
M1 cells are involved in the inflammatory response that destroys invading organisms, while M2 cells possess anti-inflammatory properties that are thought to protect against inflammatory diseases.
Researchers already know that before carrying out these roles, macrophages must first be activated and transformed into either the M1 or M2 subtype. However, the mechanism that enables this to be achieved is not fully understood.
As reported in Nature Immunology, the current study has identified the protein that drives macrophages to differentiate into the M2 type that protects against inflammatory conditions.
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.
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.”
Sujin King, Lead Author
Now, the has team investigated a cell signaling pathway called mTOR, which is known to drive macrophages to form the M2 type.
The researchers used a chemical inhibitor to stop the activity of the mTOR protein using, which enabled them to observe how other proteins in the pathway were affected.
Interestingly, the study led them to a protein called Sema6D, which is mainly known for its role in guiding neurons during nervous system development.
When the team genetically engineered M2 macrophages that did not contain Sema6D, they found the cells could no longer absorb fatty acids properly from their environment.
Without this energy source, the macrophages were unable to undergo transformation into the M2 subtype.
Once the researchers realised they could block M2 differentiation, they investigated how this might affect the protective role of these cells in inflammatory conditions.
“Using a model that mimics colitis, we found that mice lacking Sema6D have much more severe symptoms,” says Kang.
“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.”
Lead investigator Atsushi Kumanogoh says the findings suggest that Sema6D dysfunction prevents M2 differentiation, which makes the body more susceptible to inflammatory conditions.
We’re hopeful that this discovery offers new leads in the drug discovery process for these diseases.”
Atsushi Kumanogoh, Lead Investigator
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