![]() In 1970, these proteins were given the name heat shock proteins by Alfred Tissières and colleagues. In the early 1960s, Ferruccio Ritossa observed the formation of new puffs in the chromosomes of Drosophila larvae upon exposure to increased temperature. Understanding how these signaling networks come together may ultimately result in new therapeutic approaches to target molecular chaperones and/or down-stream checkpoints in controlling immune cell fate for better disease treatment. However, the roles of HSPs in metabolic and epigenetic reprogramming of immune cell function and the underlying mechanisms are still unclear. The interplay between metabolism and epigenetic adaptions has been suggested to support immune cell homeostasis. Several studies have demonstrated that molecular chaperones could affect epigenetic variation to influence numerous transcriptional programs contributing to the phenotypic plasticity of cells. Molecular chaperones have been widely investigated in regard to cancer metabolism and the inflammatory microenvironments, where they act as signals to regulate immunity and inflammation. Recent evidence has shown that certain cellular metabolism-derived metabolites have cytokine-like (e.g., succinate, itaconate) and epigenetic roles (e.g., alpha-ketoglutarate (α-KG) and acetyl coenzyme A (acetyl-CoA)) in immune responses, highlighting the role of metabolic adaptation in modulating immunity in human diseases such as infection, cancer and inflammatory disorders. In contrast, other immune cells like M2 macrophages, regulatory T cells (Tregs), and memory T cells employ oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to meet their energy demands. In general, as they respond to immunological stimulations, pro-inflammatory immune cells such as M1 macrophages, activated dendritic cells (DCs), neutrophils and effector Th1 cells adopt aerobic glycolysis (also known as the Warburg effect) to support rapid ATP production and the biosynthetic process. They adopt distinct metabolic states to support both the energetic and biosynthetic demands of a range of processes. Immune cells are highly heterogeneous in population and dynamic in functional activities. HSPs, therefore, are indicated as active players in both innate and adaptive immunity and have been evaluated as therapeutic targets in a variety of human diseases. Secreted and extracellular chaperones are able to act as ligands to bind with specific receptors on immune cells, allowing for participation in immune activities such as antigen presentation, immune cell activation and immunomodulation. In addition to preventing pathological aggregation of target proteins/peptides, growing reports have proposed that molecular chaperones can function as intracellular signals to regulate immunity and inflammation. Based on their molecular weight, these proteins have been classified into six major families including HSP100, HSP90, HSP70, HSP60, HSP40 and small heat shock proteins (sHSPs). Thus, they were initially identified as heat shock proteins (HSPs). Although constitutively expressed under steady-state, many chaperones are up-regulated by cellular stressors including high temperature. Molecular chaperones play a pivotal role in the maintenance of cellular proteostasis by preventing the misfolding and aggregation of nascent polypeptides by ensuring proper protein folding. In this review, we discuss the available data on the biological function of molecular chaperones to immune responses during inflammation, with a specific focus on the interplay between molecular chaperones and metabolic pathways that drive immune cell fate and function. However, whether molecular chaperones can regulate metabolic programs to influence immune activity is still largely unclear. Growing evidence has accumulated to indicate that metabolic pathways and their metabolites influence the function of immune cells and can alter transcriptional activity through epigenetic modification of (de)methylation and (de)acetylation. They have been identified as important participants in immune functions including antigen presentation, immunostimulation and immunomodulation, and play crucial roles in metabolic rewiring and epigenetic circuits. Molecular chaperones belong to the heat shock protein (HSP) family. Molecular chaperones are a set of conserved proteins that have evolved to assist the folding of many newly synthesized proteins by preventing their misfolding under conditions such as elevated temperatures, hypoxia, acidosis and nutrient deprivation.
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