Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function

Abstract

Lactate and the associated H⁺ ions are still introduced in many biochemistry and general biology textbooks and courses as a metabolic by-product within fast or oxygen-independent glycolysis. However, the role of lactate as a fuel source has been well-appreciated in the field of physiology, and the role of lactate as a metabolic feedback regulator and distinct signaling molecule is beginning to gain traction in the field of immunology. We now know that while lactate and the associated H⁺ ions are generally immunosuppressive negative regulators, there are cell, receptor, mediator, and microenvironment-specific effects that augment T helper (Th)17, macrophage (M)2, tumor-associated macrophage, and neutrophil functions. Moreover, we are beginning to uncover how lactate and H⁺ utilize different transporters and signaling cascades in various immune cell types. These immunomodulatory effects may have a substantial impact in cancer, sepsis, autoimmunity, wound healing, and other immunomodulatory conditions with elevated lactate levels. In this article, we summarize the known effects of lactate and H⁺ on immune cells to hypothesize potential explanations for the divergent inflammatory vs. anti-inflammatory effects.

Keywords: M2; Th17; immune; immunometabolism; immunosuppression; inflammation; lactate; lactic acid.

Figure 1

Signaling mechanisms of lactate by cell type. (A) Monocytes and macrophages, (B) Mast cells, (C) CD8+ T cells, and (D) CD4+ T cells. Figure created with BioRender.com.

Figure 2

Lactate has many immune cell-specific effects, ranging from general immunosuppression to Th17 and M2 polarization. “↑” indicates a positive signal or induction, “↓” indicates a negative signal or inhibition, and “PICs” indicates “pro-inflammatory cytokines.” Figure created with BioRender.com.