From fever to immunity: A new role for IGFBP‐6?

Abstract

Fever is a fundamental response to infection and a hallmark of inflammatory disease, which has been conserved and shaped through millions of years of natural selection. Although fever is able to stimulate both innate and adaptive immune responses, the very nature of all the molecular thermosensors, the timing and the detailed mechanisms translating a physical trigger into a fundamental biological response are incompletely understood. Here we discuss the consequence of hyperthermic stress in dendritic cells (DCs), and how the sole physical input is sensed as an alert stimulus triggering a complex transition in a very narrow temporal window. Importantly, we review recent findings demonstrating the significant and specific changes discovered in gene expression and in the metabolic phenotype associated with hyperthermia in DCs. Furthermore, we discuss the results that support a model based on a thermally induced autocrine signalling, which rewires and sets a metabolism checkpoint linked to immune activation of dendritic cells. Importantly, in this context, we highlight the novel regulatory functions discovered for IGFBP‐6 protein: induction of chemotaxis; capacity to increase oxidative burst and degranulation of neutrophils, ability to induce metabolic changes in DCs. Finally, we discuss the role of IGFBP‐6 in autoimmune disease and how novel mechanistic insights could lead to exploit thermal stress‐related mechanisms in the context of cancer therapy.

Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors

“…This result suggests that DCs’ maturation not only depends on danger signals with HSPs but also on hyperthermia itself independently ( 61 ). Further studies proposed that fever-range hyperthermia promote DCs from a quiescent status to an activated status by promoting the metabolic reprogramming in them ( 62 , 63 ). The authors proposed that hyperthermia increased the expression of insulin-like growth factor binding protein 6 (IGFBP-6) and HSP70, whose autocrine mechanism increases the glycolysis, decreases the activity of the mitochondrial respiratory chain and consequent oxidative phosphorylation (OxPhos), enhances the production of NO and ROS, and promotes the mitochondrial Ca 2+ overload.…”

Insulin-Like Growth Factor Binding Protein 6 Is Secreted in Extracellular Vesicles upon Hyperthermia and Oxidative Stress in Dendritic Cells But Not in Monocytes

“…Such activities are complemented and integrated by the effects given by IGFBP-6 independently on IGF-II, including regulation of proliferation, apoptosis, angiogenesis, and cell migration [2,3]. Recently, a role of IGFBP-6 in inflammatory reactions and diseases has been delineated [4]. We have shown that IGFBP-6 has chemoattractant properties toward cells of the innate (neutrophils, monocytes) and adaptive (T cells) immunity [5,6].…”

The Effect of Diabetes Mellitus on IGF Axis and Stem Cell Mediated Regeneration of the Periodontium

“…IGFBP-6 functions include inhibition of IGF-2 dependent cell division, migration, differentiation and survival in addition to inhibiting cell proliferation and stimulating apoptosis independently of IGF-2 [ 228 ]. IGFBP-6 also holds intracellular function through binding to nuclear and possibly mitochondrial receptors as well [ 229 ].…”