Furthermore, the chronic infection stage of T  congolense is domi

Furthermore, the chronic infection stage of T. congolense is dominated by anti-inflammatory cytokines, such as IL-4, IL-10 [24] and possibly also TGF-β. Indeed, to limit inflammatory pathogenicity and premature death of the host, Plasmodium species induce a similar switch to an anti-inflammatory environment, whereby TGF-β plays an essential role [39], suggesting that a comparable mechanism might be important during Trypanosoma infections. Besides IL-4, also various M1- and M2-associated stimuli induce Cldn2 mRNA, and thus, its association with classical or alternative macrophage activation is less clear. In vivo, macrophage

Cldn2 induction levels during parasitic infections are minor compared with the high claudin-2 mRNA levels observed check details in TAMs. In comparison with the full

set of genes tested and published in TS/A TAM [25], claudin-2 situates amongst the top 30% in terms of fold upregulation compared to PEM. The mechanisms underlying the strong association of claudin-2 mRNA with TAM remain unclear. Possibly, the complex mixture of stimuli present within the tumour microenvironment is more appropriate for optimal Cldn2 induction, as opposed to the herein www.selleckchem.com/products/jq1.html tested triggers in vitro. Hence, while Cldn2 is not appropriate to distinguish between bona fide CAMs or AAMS, this tight junction–associated gene could be used as a tumour-associated macrophage marker. IL-4 was identified as most potent Cldn11 inducer in all macrophage types tested, and this effect was nearly absent in STAT6-deficient macrophages. In agreement with our findings, Cldn11 was listed before as IL-4-inducible gene in mouse BMDM [22]. Importantly, IFN-γ and LPS did

not affect Cldn11 expression levels. Hence, claudin-11 behaves like a typical marker gene for mouse AAMs. This conclusion is corroborated in vivo, where claudin-11 mRNA is only significantly induced in typical IL-4/IL-13-induced AAMs isolated during the chronic stage of T. crassiceps helminth infections, but not in TAMs or macrophages from Trypanosoma-infected heptaminol mice. In this respect, Cldn11 seems to be a marker gene for AAMs that develop in a polarized Th2 cytokine environment and not for M2 that develop in a more complex environment like a tumour. Overall, we identified the tight junction component claudin-11 as a novel IL-4-induced gene in AAMs. Cldn1 is mainly associated with TGF-β-activated macrophages, and hence, Cldn1 expression could be used as a tracer for TGF-β-exposed macrophages. Finally, Cldn2 can be induced in macrophages by various stimuli in vitro and is abundantly expressed in vivo by tumour-associated macrophages. The authors thank Ella Omasta, Marie-Thérèse Detobel, Nadia Abou, Lea Brys and Eddy Vercauteren for their technical aid. This work was supported by a doctoral grant from ‘FWO-Vlaanderen’ to J.V.d.B and K.M.

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