Immunometabolism Flashcards
Why is immunometabolism important for immune cells?
Immunometabolism is very important for all immune cells, for example T cells. It is important for their survival, proliferation and differentiation. Different immune cells require a bit different metabolism:
- memory and regulatory T cells rely more on oxidative phosphorylation - effector T cells on glycolysis
Can immunometabolism be used as therapeutic target?
Yes, potentially cells can be switched to other less inflammatory subtypes. For example switching th1 cells into Tregs. However, for example switching it in cancer patients leads to autoimmunity so here it could potentially lead to malignancies and higher susceptibility to infections.
What is lactate?
Lactate is the most abundant metabolite in the microenvironment e.g. synovium of RA patients. It is immunomodulatory metabolite and there are both receptors and transporters of lactate. We could potentially target both production and sensing of lactate. Accumulation of lactate is bad for both cancer and autoimmunity. What we want is to either reduce the amount of lactate or reduce the response to lactate.
Lactate and autoimmunity?
When CD4 T cells enter inflammatory sites they up regulate SLC5A12 transporter which is a lactate transporter. This way CD4 T cells can uptake more lactate which contributes to metabolism:
- Impacts migration of T cells. This leads to T cells being trapped in the inflammatory site
- Activates pathways which lead to production of pro-inflammatory cytokines (IL-17, IL-21)
Blocking SLC5A12 leads to lower T cell infiltration and loss of IL-17 but gain of IL-10.
How does lactate change T cell metabolism?
Lactate converts to AcetylCoA, leading to its accumulation. AcetylCoA can be used for acetylation which is a post-translational modification and change activity of the protein. Also, carbons of lactate can be used for biosynthesis of fatty acids. Lactate also leads to increased production of IL-21
Atherosclerosis
Atherosclerosis is mainly driven by CD4 T cells and is is a hypoxic environment with lactate accumulation.
SLC5A12 is unregulated in atherosclerotic lesions. It is unregulated only in the tissue and not in the blood, making SLC5A12 a potential target for atherosclerosis treatment.
In mice KO of SLC5A12 decreases atherosclerotic lesions and leads to decreased IL-17 and IL-12 but increased Tregs
