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Anti-TNF agents restrict AIEC replication within macrophages in patients with Crohn’s disease.


12 January 2022

Université Clermont Auvergne, France.

Clara Douadi, Emilie Vazeille, Christophe Chambon, Michel Hébraud, Margot Fargeas, Marie Dodel, Dilek Coban, Bruno Pereira, Aurélien Birer, Pierre Sauvanet, Anthony Buisson, Nicolas Barnich

Anti-TNF agents restrict adherent-invasive Escherichia coli replication within macrophages through modulation of chitinase 3-like 1 in patients with Crohn's disease

Background & aims:

The mechanism of action of anti-TNF agents could implicate macrophages modulation in Crohn's disease (CD). As CD macrophages are defective to control CD-associated adherent-invasive E. coli (AIEC), anti-TNF agents could limit AIEC replication within macrophages. We assessed the effect of anti-TNF agents on AIEC survival within monocytes-derived macrophages (MDM) from CD patients and attempted to identify the implicated proteins.

Peripheral blood monocyte-derived macrophages (MDM) were obtained from 44 CD patients including 22 with and 22 without anti-TNF agents. MDM were infected with AIEC-LF82 reference strain. Proteomic analysis was performed before and 6h after AIEC-LF82 infection.

AIEC-LF82 survival was lower in MDM from CD patients receiving anti-TNF agents compared to those who did not (-73%, p=0.006). After AIEC-LF82 infection, the levels of CD82 (p=0.007), ILF3 (Interleukin enhancer-binding factor 3; p=0.001), FLOT-1 (Flotillin-1; p=0.007) and CHI3L1 (Chitinase 3-like 1; p=0.035) proteins were different within CD-MDM depending on anti-TNF exposure. FLOT-1 (ϱ=- 0.44; p=0.038) and CHI3L1 (ϱ=0.57, p=0.006) levels were inversely and positively correlated with AIEC survival within MDM from CD patients with or without anti-TNF, respectively. We observed a dose-dependent decrease of AIEC-LF82 survival after adjunction of anti-TNF within MDM inducing increase of FLOT-1 and decrease of CHI3L1 mRNA levels. Neutralization of intra-macrophagic CHI3L1 protein using anti-CHI3L1 antibodies reduced AIEC survival within macrophages 6h after infection (p<0.05).

Anti-TNF agents are able to restrict replication of pathobiont, such as AIEC, within macrophages by modulating FLOT-1 and CHI3L1 expressions in CD patients.