Lactate: Fueling the fire starter

Abstract

It is becoming increasingly appreciated that intermediates of metabolic pathways, besides their anabolic and catabolic functions, can act as signaling molecules and influence the outcome of immune responses. Although lactate was previously considered as a waste product of glucose metabolism, accumulating evidence has highlighted its pivotal role in regulating diverse biological processes, including immune cell polarization, differentiation and effector functions. In addition, lactate is a key player in modulating tumor immune surveillance. Hence, targeting lactate-induced signaling pathways is a promising tool to reduce inflammation, to prevent autoimmunity and to restore anti-tumor immune response. This article is characterized under: Biological Mechanisms > Metabolism.

Keywords: immunity; inflammation; lactate; metabolism; tumor.

Figure 1

The history of lactate. Lactic acid was isolated for the first time by the chemist Carl Wilhelm Scheele in 1780 from sour milk. Indeed, the name lactate originates from the Latin word lac, which means milk. In 1808, Jöns Jacob Berzelius discovered that lactic acid (l‐lactate) is produced in muscles during exercise. In 1856, the role of Lactobacillus in the synthesis of lactate was discovered by Pasteur (1861) and only 20 years later in 1873 lactate molecular structure was resolved by Johannes Wislicenus (Nalbandian & Takeda, 2016). In 1923, Otto Warburg observed that cancer cells were characterized by accelerated glycolysis and excessive lactate generation even under fully oxygenated conditions (Warburg, 1956). His discovery was subsequently named the “Warburg Effect” by Efraim Racker in 1972. In 1946 lactate was identified as a major gluconeogenic precursor acting as shuttle in both muscle and liver (Cori & Cori, 1946). Later in 1954, LDH, the enzyme responsible for lactate production was found elevated in cancer (Hill & Levi, 1954) and in 1994 lactate was identified as major carbon source in the brain facilitating the interconnections between astrocytes and neurons (Pellerin & Magistretti, 1994). MCTs were firstly described as lactate transporters (Halestrap & Price, 1999) and MCT1 was later identified as target for tumor suppression (Sonveaux et al., 2008). Recent studies have emerged describing lactate as immune modulator in inflammatory disorders and as key carbon fuel for some tumors (Colegio et al., 2014; Faubert et al., 2017; Haas et al., 2015; Hui et al., 2017; Pucino et al., 2019)

Figure 2

Lactate modulates immune cell functions in immune‐mediated inflammatory disorders and cancer. Immune cells “sense” high concentration of lactate which accumulates at the site of inflammation or tumor as result of accelerated metabolism of immune, stromal, or cancer cells. Lactate is taken up through specific transporters expressed on the cell membrane and modulates immune responses, including activation, differentiation, proliferation, migration, and cytokine production. These events promote the establishment of a chronic inflammatory process in IMIDs and induce tumor growth and metastatic spread in cancer