Author:
Bracho-Sanchez Evelyn,Rocha Fernanda,Bedingfield Sean,Partain Brittany D.,Brusko Maigan A.,Colazo Juan M.,Fettis Margaret M.,Farhadi Shaheen A.,Helm Eric,Koenders Kevin,Kwiatkowski Alexander J.,Macias Sabrina L.,Restuccia Antonietta,Wanchoo Arun,Avram Dorina,Allen Kyle D.,Duvall Craig L.,Wallet Shannon M.,Hudalla Gregory A.,Keselowsky Benjamin G.
Abstract
Summary paragraphChronic inflammation underlies the onset, progression and associated pain of numerous diseases.(1) Current anti-inflammatory treatments administered systemically are associated with moderate-to-severe side effects, while locally administered drugs have short-lived efficacy, and neither approach successfully modifies the underlying causality of disease.(2) We report a new way to locally modulate inflammation by fusing the enzyme indoleamine 2,3-dioxygenase 1 (IDO) to galectin-3 (Gal3). A general regulator of inflammation(3), IDO is immunosuppressive(4), catabolizing the essential amino acid tryptophan into kynurenine.(5) Recently we demonstrated that extracellular exogenous IDO regulates innate immune cell function(6), and envisioned delivering IDO into specific tissues would provide control of inflammation. However, proteins problematically diffuse away from local injection sites. Addressing this, we recently established that fusion to Gal3 anchors enzymes to tissues(7) via binding to extracellular glycans. Fusion protein IDO-Gal3 was retained in injected tissues and joints for up to a week or more, where it suppressed local inflammation in rodent models of endotoxin-induced inflammation, psoriasis, periodontal disease and osteoarthritis. Amelioration of local inflammation, disease progression and inflammatory pain were concomitant with homeostatic preservation of tissues without global immune suppression. Thus, IDO-Gal3 presents a new concept of anchoring immunomodulatory enzymes for robust control of focal inflammation in multiple disease settings.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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