Immunometabolic Approaches Mitigating Foreign Body Response and Transcriptome Characterization of the Foreign Body Capsule.

Directing immunometabolism presents new opportunities to modulate key cell types associated with the formation of foreign body response (FBR) capsule. Contrasting approaches directing immunometabolism are investigated to mitigate FBR: a broadly suppressive metabolic inhibitor (MI) cocktail comprised of 2-deoxyglucose (2-DG), metformin, and 6-diazo-5-oxo-l-norleucine (DON) with daily systemic dosing regimen, and local weekly injection of the more narrowly focused tryptophan catabolizing IDO-Gal3 fusion protein. Treatments significantly decrease FBR capsule formed around subcutaneously implanted cellulose disks. MI cocktail results in a substantially thinner FBR capsule (40% of control), while weekly local injection of IDO-Gal3 also results in a thinner FBR capsule (69% of control). RNA-sequencing capsule transcripts reveal MI cocktail promotes quiescence, with decreased antigen processing and presentation, T helper subset differentiation, and cytokine-cytokine receptor pathway. IDO-Gal3 promotes pro-regenerative, alternatively activated M2-like macrophages and T helper 2 cells, with increased expression of type 2 response-associated genes (Il4, Il13, Arg1, Mrc1, Chil3, Gata3). IDO-Gal3 decreases pro-inflammatory innate sensing pathways, and C-type lectin receptor, NOD-like receptor, RIG-I-like receptor, and Toll-like receptor signaling. This work helps define key gene targets and pathways concomitantly regulated in the FBR capsule during immunometabolic modulation compared to control FBR capsule.

Suppression of local inflammation via galectin-anchored indoleamine 2,3-dioxygenase.

The treatment of chronic inflammation with systemically administered anti-inflammatory treatments is associated with moderate-to-severe side effects, and the efficacy of locally administered drugs is short-lived. Here we show that inflammation can be locally suppressed by a fusion protein of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO) and galectin-3 (Gal3). Gal3 anchors IDO to tissue, limiting the diffusion of IDO-Gal3 away from the injection site. In rodent models of endotoxin-induced inflammation, psoriasis, periodontal disease and osteoarthritis, the fusion protein remained in the inflamed tissues and joints for about 1 week after injection, and the amelioration of local inflammation, disease progression and inflammatory pain in the animals were concomitant with homoeostatic preservation of the tissues and with the absence of global immune suppression. IDO-Gal3 may serve as an immunomodulatory enzyme for the control of focal inflammation in other inflammatory conditions.

Perspectives on immunometabolism at the biomaterials interface.

Productive engagement of the immune system is a persistent challenge for biomaterials scientists. Immune engineering offers a new perspective on biomaterial design, with immune cell interaction to modulate effector functions at the center. The effector functions of these cells are intimately linked to their metabolic needs and programming. Immune cell metabolism has received renewed attention in recent years, and with each new discovery there is opportunity for biomaterials scientists. This prospectus aims to provide an overview of the most recent advances in biomaterial engagement of immune cells alongside interrogation of immunometabolism, while looking to future avenues of coalescence. Four cell types are highlighted here: neutrophils, macrophages, dendritic cells, and T cells. Consideration of these two fields, and the tools within each, with a forward-looking mindset is the key to a new era of biomaterials.