IDO activation, inflammation and musculoskeletal disease

Abstract

The IDO/kynurenine pathway is now established as a major regulator of immune system function. The initial enzyme, indoleamine 2,3-dioxygenase (IDO1) is induced by IFNγ, while tryptophan-2,3-dioxygenase (TDO) is induced by corticosteroids. The pathway is therefore positioned to mediate the effects of systemic inflammation or stress-induced steroids on tissue function and its expression increases with age. Disorders of the musculoskeletal system are a common feature of aging and many of these conditions are characterized by an inflammatory state. In inflammatory arthritis and related disorders, kynurenine protects against the development of experimental arthritis, while inhibition or deletion of IDO1 increases its severity. The longterm regulation of autoimmune disorders may be influenced by the epigenetic modulation of kynurenine pathway genes, with recent data suggesting that methylation of IDO may be involved. Osteoporosis is also associated with abnormalities of the kynurenine pathway, reflected in an inversion of the ratio between blood levels of the metabolites anthranilic acid and 3-hydroxy-anthranilic acid. This review discusses evidence to date on the role of the IDO/kynurenine pathway and the highly prevalent age-related disorders of osteoporosis and rheumatoid arthritis and identifies key areas that require further research.

Physical Activity and Diet Shape the Immune System during Aging

“…These results were in accordance with earlier findings that reported that inflammation causes the upregulation of IDO activity and leads to increased tryptophan catabolism via the kynurenine pathway [68]. On the other hand, in inflammatory arthritis and related disorders, kynurenine protects against the development of disease, while the inhibition or deletion of IDO increases its severity [84]. Similarly, the results from a recent study in hemodialysis patients suggested that the low tryptophan values in this patient group could not be attributed to high IDO activity or an inflammatory state [85].…”

Immune Influencers in Action: Metabolites and Enzymes of the Tryptophan-Kynurenine Metabolic Pathway

“…In addition, an increased TDO expression was described in many tumor types, for example, breast cancer, melanoma or lung cancer [35,36] (Table 1). The main determinant of TRP availability is the TDO enzyme, the expression of TDO can be stimulated by estrogens, corticosteroids, heme, as well as TRP itself [35,56,57]. NADH and NADPH inhibit TDO expression through a negative feedback loop [54] (Table 1, Figure 3).…”

The prevalence of sarcopenia in patients with rheumatological pathology

“…В настоящее время согласно EWGSOP2 в зависимости от этиологии саркопению подразделяют на первичную (agerelated sarcopenia -возрастассоциированную саркопению) и вторичную саркопению (disease-related sarcopenia -саркопению, ассоциированную с заболеванием) [5,7,8]. Основным патогенетическим механизмом развития вторичной саркопении является стойкое повышения уровня провоспалительных цитокинов в крови, в том числе интерлейкина-6, фактора некроза опухоли α. В связи с этим особый интерес представляет оценка распространенности саркопении у пациентов с ревматологической патологией, для которых в целом характерно значительное стойкое повышение уровня провоспалительных цитокинов [9].…”