Lactate at the crossroads of metabolism, inflammation, and autoimmunity

Abstract

For a long time after its discovery at the beginning of the 20th century, lactate was considered a waste product of cellular metabolism. Starting in the early '90s, however, lactate has begun to be recognized as an active molecule capable of modulating the immune response. Inflammatory sites, including in rheumatoid arthritis (RA) synovitis, are characterized by the accumulation of lactate, which is partly responsible for the establishment of an acidic environment. We have recently reported that T cells sense lactate via the expression of specific transporters, leading to inhibition of their motility. Importantly, this "stop migration signal" is dependent upon lactate's interference with intracellular metabolic pathways, specifically glycolysis. Furthermore, lactate promotes the switch of CD4 + T cells to an IL-17 + subset, and reduces the cytolytic capacity of CD8 + T cells. These phenomena might be responsible for the formation of ectopic lymphoid structures and autoantibody production in inflammatory sites such as in RA synovitis, Sjogren syndrome salivary glands, and multiple sclerosis plaques. Here, we review the roles of lactate in the modulation of the inflammatory immune response.Keywords: Arthritis r Inflammation r Lactate r Metabolism r T cells Crosstalk between immunity and metabolismThe immune system is constituted of a heterogeneous population of immune cells, which are able to respond to inflammatory stimuli upon switching from a quiescent to an activated status. These responses are tightly regulated by a wide range of cell type specific receptors and transcription factors. In immune cells this determines changes in the expression of large numbers of genes and results in the acquisition of new functions, such as the production of cytokines, lipid mediators and metabolites as well as the ability to proliferate, differentiate into specialized subtypes and migrate to target tissues. All such functions require the supply of nutrients into different metabolic pathways. In the last few yearsCorrespondence: Dr. Claudio Mauro e-mail: c.mauro@qmul.ac.uk there has been an increasing appreciation of how such metabolic pathways integrate with and in fact determine specific immune cell responses [1]. T-cell metabolism, inflammation, and autoimmunityIn the past few years, metabolism has been in the spotlight because of its pivotal role in disorders such as cancer as well as inflammatory and autoimmune diseases. Many studies have highlighted how cancer cells rely upon bioenergetic pathways to support their growth. As for cancer cells, immune cells also adapt their metabolic status as a consequence to changes in the external microenvironment (i.e. inflammation). T cells are key players of adaptive immunity and have high metabolic demand for their activation, proliferation, differentiation in specific cell subsets, and migration to target organs, while quiescent T cells rely mainly Alterations of this fine tuning between metabolism and immunity might lead to an unbalance between pro-and anti-inflammatory responses ...

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

“…Furthermore, expression of the lactate transporter SLC5a12 in synovial tissue was shown to correlate with the clinical T cell score, and in-vivo blockade of lactate transporters resulted in the release of T cells from the inflammatory site [28]. These findings provide a rationale for the therapeutic targeting of specific lactate transporters on T cells in autoimmune diseases such as RA (reviewed in [38]). These findings provide a rationale for the therapeutic targeting of specific lactate transporters on T cells in autoimmune diseases such as RA (reviewed in [38]).…”

“…These data suggest that the elevated lactate concentrations observed in the RA joint inhibit the glycolysis and migration of effector T cells, resulting in their retention at the site of inflammation and also increasing their production of IL-17. These findings provide a rationale for the therapeutic targeting of specific lactate transporters on T cells in autoimmune diseases such as RA (reviewed in [38]). Consistent with this, expression levels of the lactate transporter MCT4 and glycolytic enzymes HK2, GPI, triosephosphate isomerase (TPI), enolase 1 (Eno 1), PKM2 and LDH are significantly reduced in Th17 cells obtained from HIF1α -/compared to wild-type (WT) mice [31], demonstrating the dependence of increased glycolytic enzymatic REVIEW SERIES: TRANSLATING IMMUNOMETABOLISM activity on the oxygen sensing pathway.…”

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

“…Low glucose and high lacate has long been recognized as typical for the rheumatoid joint [58]. Extracellular pH sustains an important cell-cell communication network, as acid-sensing ion channels sense the metabolic activity of cellular partners in their direct surroundings [59]. Lactate has immediate impact on the functional behavior of T-cells [45], modifying their polarization, mobility and cytotoxic capacity.…”

Functional and phenotypic heterogeneity of Th17 cells in health and disease

“…RA is traditionally associated with the presence of rheumatoid factors and anticyclic citrullinated peptide autoantibodies . Interestingly, Th17 cells have been identified in germinal centres of ectopic lymphoid structures (ELS) in joints of RA patients . In mice, Th17 cells induce ELS in joints while germinal centre‐resident Th17 cells reduce sialylation of IgG, thus promoting pathogenic autoantibody production .…”

“…47 Interestingly, Th17 cells have been identified in germinal centres of ectopic lymphoid structures (ELS) in joints of RA patients. 58 In mice, Th17 cells induce ELS in joints while germinal centre-resident Th17 cells reduce sialylation of IgG, thus promoting pathogenic autoantibody production. 46 Relevant to the link between Th17 cells and autoantibody production is that BAFF activates both plasma cells and Th17 cells and exacerbates joint pathology.…”