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.

Keywords: T cells; cancer microenvironment; dendritic cells; fever; immune system; inflammation; mitochondrial metabolism; neutrophils.

Figure 1

Effect of mild hyperthermic stress on dendritic cells. The picture shows schematically the main results of a study18 carried out on cultured human monocyte‐derived dendritic cells (MoDCs) exposed for 3 h from 37 to 39°C. The major outcomes, observed in hyper‐thermic MoDC appear to involve the mitochondrial oxidative metabolism and consisted in decreased activity of the mitochondrial respiratory chain and consequent oxidative phosphorylation (OxPhos), enhanced production of reactive nitrogen and oxygen species (RONS) and overload of intramitochondrial (mt) Ca²⁺ ions. This was accompanied with increased glycolysis, suggesting metabolic rewiring, and release of pro‐inflammatory cytokines. All the above reported effects were re‐capitulated in normothermic MoDCs exposed to the conditioned medium of the 39°C‐treated cells thus suggesting the involvement of secretome‐contained factors. On the basis of results of a transcriptome study performed on the same cells under identical hyperthermic conditioning,21 HSP70 and IGFBP‐6 are indicated as putative candidates acting via an autocrine mechanism. The shown protein structures of IGFBP‐6 and HSP70 were taken from the RCSB‐protein data bank (http://www.rcsb.org/)

Figure 2

Extracellular actions of IGFBP‐6. IGFBP‐6 presents both IGF‐dependent and IGF‐independent actions. A subdomain of N‐terminus and the C‐terminal domain likely contribute cooperatively to the IGF‐II‐binding preference.25 By binding to IGF‐II and displacing it from its receptors (IGF‐IR, IGF type I receptor; IR‐A, insulin receptor type A; IR/IGF‐IR HR, insulin receptor/IGF receptor hybrid receptor), IGFBP‐6 inhibits IGF‐II‐induced cell proliferation, differentiation, migration and survival. The binding of IGF‐II to the IGF‐IIR/CI‐MPR (IGF receptor type II/cation‐independent mannose 6‐phpsphate receptor) is also shown leading to IGF‐II internalization and degradation. The double arrows underpin the equilibrium between IGF‐II‐bound and IGF‐II‐unbound IGFBP‐6 IGF receptors. IGFBP‐6 binding to prohibitin‐2 (PBH2) mediates IGF‐independent inhibition of cancer cell migration induced by IGFBP‐6. Other IGF‐independent actions of IGFBP‐6 are inhibition of angiogenesis, inhibition of fibroblast proliferation and induction of apoptosis. Recent evidences support that IGFBP‐6 has also a regulatory role in the immune system by inducing chemotaxis of T cells, monocytes and neutrophils (PMN), as well as by increasing oxidative burst of neutrophils. All these actions are mediated by unknown receptors. The shown protein structures of IGFBP‐6, IGF‐I, IGF‐II and IGF receptors were taken and pictorially modified from the RCSB‐protein data bank (http://www.rcsb.org/). See text for further details

Figure 3

Intracellular actions of IGFBP‐6. IGFBP‐6 is shown to be imported into the nucleus, via an α‐importin‐mediated mechanism, where it binds to VDR (vitamin D receptor) interfering with formation of the transcription complex RXR (retinoid X receptor)/VDR. Further proven interactors of IGFBP‐6 are TRα1 (thyroid hormone receptor‐α1) and H2Br (histone cluster 1 H2br). Moreover, IGFBP‐6 can bind to the promoter of EGR‐1 (early growth response‐1). In the cytoplasm, IGFBP‐6 is shown to affect the nuclear import of Ku80 (Lupus Ku autoantigen protein p80) involved with Ku70 in NHEJR (non‐homologous end join repair). In addition, it hypothesized the interaction between IGFBP‐6 and the mitochondrial PHB1/2 (prohibitions 1 and 2) complex. See text for further details