Mitochondrial electron transport chain modulation orchestrates divergent TLR3 and TLR7 responses.

Macrophages are on the front lines against viral infections and play a central role in initiating antiviral immune responses. They do this by sensing viral ligands through their arsenal of pattern recognition receptors, which fine-tune and determine the specificity of the immune response. Cellular metabolism has emerged as a central regulator of this specificity, driven in part by alterations in mitochondrial function. Yet, we are only starting to elucidate the specific mitochondrial dynamics that contribute to this differential modulation. Here, we report that TLR3 vs. TLR7 engagement results in divergent metabolic reprogramming that regulates their specific responses and that PKM2 dimerization and nuclear translocation serve as regulators of the balance in type I IFN, proinflammatory and anti-inflammatory programming. Furthermore, we found chemical modulation of ETC complexes I and II activity can selectively alter PKM2-dependent signaling, enabling a fine-tuning of macrophage effector response. Given that TLR3 and TLR7 ligands are utilized as vaccine adjuvants and have demonstrated potential as cancer immunotherapies, our findings suggest that specific targeting of mitochondrial function can be used to manipulate macrophage responses and to improve the efficacy and limit the off-target effects of these therapeutics.