Regulation of colonic epithelial cell turnover by IDO contributes to the innate susceptibility of SCID mice to Trichuris muris infection - PubMed (original) (raw)

Regulation of colonic epithelial cell turnover by IDO contributes to the innate susceptibility of SCID mice to Trichuris muris infection

L V Bell et al. Parasite Immunol. 2011 Apr.

Free PMC article

Abstract

Tryptophan catabolism via the kynurenine pathway is dependent on the enzyme Indoleamine 2,3-dioxygenase (IDO). Expression of IDO is upregulated in a number of inflammatory settings such as wounding and infection, and the resulting local tryptophan depletion may inhibit the replication of intracellular pathogens. Indo gene expression is upregulated in the gut during chronic infection with the mouse whipworm Trichuris muris. We demonstrate an increase in the rate of colonic epithelial cell turnover after inhibition of IDO in T. muris-infected SCID mice, leading to a significant expulsion of parasite burden. We identify the goblet cell as a novel source of IDO and present data revealing a new role for IDO in the regulation of epithelial cell turnover post-infectious challenge.

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Figures

Figure 1

_Trichuris muris_-infected SCID mice express Indo in the large intestine, and inhibition of IDO results in a significant parasite expulsion by day 21 p.i., along with an increase in epithelial cell turnover. SCID mice were infected with approx. 200 infective T. muris eggs and killed at day 7, 13 and 21 p.i. RNA was extracted from caecal tissue and Indo expression analysed by qPCR (a). Data are expressed as fold change over naive mice. Mice were then infected with T. muris and treated with 1-MT in drinking water from day −7 throughout infection and killed at day 21 p.i. after having been injected i.p. with 0·5 mg BrdU either 40 min or 12 h earlier. Worm burdens were assessed (b) along with the distance proliferating cells had moved up the crypt axis over a 12-h period (c, d) compared with crypt depth (e) to assess the rate of epithelial cell turnover. Black bars represent 1-MT-treated mice, and white bars represent controls (d and e). All data presented are mean ± SD for five mice per group and are representative of three experimental repeats, *U = 0·00, 5 d.f., _P_=0·0007, **H = 14·64, 4 d.f., _P_=0·0159.

Figure 2

The goblet cell is the major source of IDO in the _Trichuris muris_-infected SCID gut. SCID mice were infected with approximately 200 infective T. muris eggs and killed at day 21 p.i. IDO+ cells were identified in tissue sections by immunofluorescence (a, red = IDO+, blue = DAPI) and goblet cells stained using PAS. All images are at original magnification ×400. Goblet cells were counted per 20 ccu in three tissue sections per mouse, black bars represent 1-MT-treated mice, and white bars represent controls (b). Data are presented as mean ± SD for five mice per group and are representative of three experimental repeats. LS174T cells were stimulated with T. muris E/S at 50 μg/mL, recombinant human IFN-γ or IL-13 at 10 ng/mL and Indo expression assessed by qPCR (c). Data are expressed as fold change over unstimulated cells and are representative of three experimental repeats, *U = 0·00, 5 d.f., _P_= 0·0159 and **U = 0·00, 5 d.f., _P_= 0·0079.

References

1. Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J. 1991;5:2516–2522. - PubMed
1. Munn DH, Shafizadeh E, Attwood JT, et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999;189:1363–1372. - PMC - PubMed
1. Hwu P, Du MX, Lapointe R, et al. Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol. 2000;164:3596–3599. - PubMed
1. Silva NM, Rodrigues CV, Santoro MM, et al. Expression of indoleamine 2,3-dioxygenase, tryptophan degradation, and kynurenine formation during in vivo infection with Toxoplasma gondii: induction by endogenous gamma interferon and requirement of interferon regulatory factor 1. Infect Immun. 2002;70:859–868. - PMC - PubMed
1. Fujigaki S, Saito K, Takemura M, et al. L-tryptophan-L-kynurenine pathway metabolism accelerated by Toxoplasma gondii infection is abolished in gamma interferon-gene-deficient mice: cross-regulation between inducible nitric oxide synthase and indoleamine-2,3-dioxygenase. Infect Immun. 2002;70:779–786. - PMC - PubMed

Regulation of colonic epithelial cell turnover by IDO contributes to the innate susceptibility of SCID mice to Trichuris muris infection - PubMed (original) (raw)