PT  - JOURNAL ARTICLE
AU  - Evelyn Bracho-Sanchez
AU  - Fernanda Rocha
AU  - Sean Bedingfield
AU  - Brittany D. Partain
AU  - Maigan A. Brusko
AU  - Juan M. Colazo
AU  - Margaret M. Fettis
AU  - Shaheen A. Farhadi
AU  - Eric Helm
AU  - Kevin Koenders
AU  - Alexander J. Kwiatkowski
AU  - Sabrina L. Macias
AU  - Antonietta Restuccia
AU  - Arun Wanchoo
AU  - Dorina Avram
AU  - Kyle D. Allen
AU  - Craig L. Duvall
AU  - Shannon M. Wallet
AU  - Gregory A. Hudalla
AU  - Benjamin G. Keselowsky
TI  - Galectin-anchored indoleamine 2,3-dioxygenase suppresses local inflammation
AID  - 10.1101/2021.05.07.443161
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.07.443161
4099  - http://biorxiv.org/content/early/2021/05/09/2021.05.07.443161.short
4100  - http://biorxiv.org/content/early/2021/05/09/2021.05.07.443161.full
AB  - Chronic 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.Competing Interest StatementBGK and GAH are founders, hold stock and serve on the scientific advisory board of Anchor Biologics, Inc. The University of Florida has filed patents related to molecules and their uses reported in this paper.