Targeting ulcerative colitis by suppressing glucose uptake with ritonavir.

ABSTRACT: Glucose is the preferred source of energy in activated inflammatory cells. Glucose uptake into the cell is ensured by a family of glucose uptake transporters (GLUTs), which have been identified as off-target molecules of the HIV protease inhibitor ritonavir. In this study, we examined the effect of ritonavir on inflammation in vitro and in vivo Peripheral blood mononuclear cells (PBMCs) were activated with anti-CD3 in the presence or absence of ritonavir and analyzed by flow cytometric analysis. Frequencies of CD4+ cells were significantly affected by ritonavir (CD69+ P=3E-05; CD134 P=4E-06; CD25+ P=E-07; central memory P=0.02; effector P=6E-03; effector memory P=6E-05). To corroborate that inflammation has a metabolic effect in vivo, a mouse model was used that is based on immunocompromised NOD-scid IL-2R? ?null mice reconstituted with PBMCs from patients with ulcerative colitis (UC). Inflammation had a significant effect on amino acid (AA) levels (Glu P=1E-07, Asp P=1E-04). Principal component analysis (PCA) discriminated between unchallenged and challenged groups. Finally, the efficacy of ritonavir was tested in the same mouse model. Dependent variables were clinical and histological scores, frequencies of human leukocytes isolated from spleen and colon, and levels of AA in sera of mice. Mice benefited from treatment with ritonavir as indicated by significantly decreased colon (P=7E-04) and histological (P=1E-04) scores, frequencies of M2 monocytes (CD14+ CD163; P=0.02), and Glu levels (P=2E-05). PCA discriminated between control and challenged groups (P=0.026). Thus, inhibition of glucose uptake might be a promising therapeutic intervention point for active UC.

SUBMITTER: Jodeleit H 

PROVIDER: S-EPMC6262818 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature