Background Cachexia, a multifactorial syndrome affecting more than 50% of patients with advanced cancer and responsible for ~20% of cancer‐associated deaths, is still a poorly understood process without a standard cure available. Skeletal muscle atrophy caused by systemic inflammation is a major clinical feature of cachexia, leading to weight loss, dampening patients' quality of life, and reducing patients' response to anticancer therapy. RAGE (receptor for advanced glycation end‐products) is a multiligand receptor of the immunoglobulin superfamily and a mediator of muscle regeneration, inflammation, and cancer. Methods By using murine models consisting in the injection of colon 26 murine adenocarcinoma (C26‐ADK) or Lewis lung carcinoma (LLC) cells in BALB/c and C57BL/6 or Ager −/− (RAGE‐null) mice, respectively, we investigated the involvement of RAGE signalling in the main features of cancer cachexia, including the inflammatory state. In vitro experiments were performed using myotubes derived from C2C12 myoblasts or primary myoblasts isolated from C57BL/6 wild type and Ager −/− mice treated with the RAGE ligand, S100B (S100 calcium‐binding protein B), TNF (tumor necrosis factor)α±IFN (interferon) γ, and tumour cell‐ or masses‐conditioned media to analyse hallmarks of muscle atrophy. Finally, muscles of wild type and Ager −/− mice were injected with TNFα/IFNγ or S100B in a tumour‐free environment. Results We demonstrate that RAGE is determinant to activate signalling pathways leading to muscle protein degradation in the presence of proinflammatory cytokines and/or tumour‐derived cachexia‐inducing factors. We identify the RAGE ligand, S100B, as a novel factor able to induce muscle atrophy per se via a p38 MAPK (p38 mitogen‐activated protein kinase)/myogenin axis and STAT3 (signal transducer and activator of transcription 3)‐dependent MyoD (myoblast determination protein 1) degradation. Lastly, we found that in cancer conditions, an increase in serum levels of tumour‐derived S100B and HMGB1 (high mobility group box 1) occurs leading to chronic activation/overexpression of RAGE, which induces hallmarks of cancer cachexia (i.e. muscle wasting, systemic inflammation, and release of tumour‐derived pro‐cachectic factors). Absence of RAGE in mice translates into reduced serum levels of cachexia‐inducing factors, delayed loss of muscle mass and strength, reduced tumour progression, and increased survival. Conclusions RAGE is a molecular determinant in inducing the hallmarks of cancer cachexia, and molecular targeting of RAGE might represent a therapeutic strategy to prevent or counteract the cachectic syndrome.

Emerging evidence suggests that the signalling of the Receptor for Advanced Glycation End products (RAGE) is critical for skeletal muscle physiology controlling both the activity of muscle precursors during skeletal muscle development and the correct time of muscle regeneration after acute injury. On the other hand, the aberrant re‐expression/activity of RAGE in adult skeletal muscle is a hallmark of muscle wasting that occurs in response to ageing, genetic disorders, inflammatory conditions, cancer, and metabolic alterations. In this review, we discuss the mechanisms of action and the ligands of RAGE involved in myoblast differentiation, muscle regeneration, and muscle pathological conditions. We highlight potential therapeutic strategies for targeting RAGE to improve skeletal muscle function.

The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein.

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