التفاصيل البيبلوغرافية
| العنوان: |
IL-4 and helminth infection downregulate MINCLE-dependent macrophage response to mycobacteria and Th17 adjuvanticity. |
| المؤلفون: |
Schick, Judith1, Altunay, Meltem1, Lacorcia, Matthew2,3, Marschner, Nathalie1, Westermann, Stefanie4, Schluckebier, Julia2,3, Schubart, Christoph4, Bodendorfer, Barbara1, Christensen, Dennis5, Alexander, Christian6, Wirtz, Stefan7, Voehringer, David4, Prazeres da Costa, Clarissa2,3, Lang, Roland1 roland.lang@uk-erlangen.de |
| المصدر: |
eLife. 2/8/2023, p1-24. 24p. |
| مصطلحات موضوعية: |
*HELMINTHIASIS, *MYCOBACTERIUM bovis, *NEMATODE infections, *MACROPHAGES, *MYCOBACTERIA, *MYCOBACTERIAL diseases |
| مستخلص: |
The myeloid C-type lectin receptor (CLR) MINCLE senses the mycobacterial cell wall component trehalose-6,6'- dimycolate (TDM). Recently, we found that IL-4 downregulates MINCLE expression in macrophages. IL-4 is a hallmark cytokine in helminth infections, which appear to increase the risk for mycobacterial infection and active tuberculosis. Here, we investigated functional consequences of IL-4 and helminth infection on MINCLE-driven macrophage activation and Th1/Th17 adjuvanticity. IL-4 inhibited MINCLE and cytokine induction after macrophage infection with Mycobacterium bovis bacille Calmette-Guerin (BCG). Infection of mice with BCG upregulated MINCLE on myeloid cells, which was inhibited by IL-4 plasmid injection and by infection with the nematode Nippostrongylus brasiliensis in monocytes. To determine the impact of helminth infection on MINCLE-dependent immune responses, we vaccinated mice with a recombinant protein together with the MINCLE ligand trehalose-6,6-dibehenate (TDB) as adjuvant. Concurrent infection with N. brasiliensis or with Schistosoma mansoni promoted T cell-derived IL-4 production and suppressed Th1/Th17 differentiation in the spleen. In contrast, helminth infection did not reduce Th1/Th17 induction by TDB in draining peripheral lymph nodes, where IL-4 levels were unaltered. Upon use of the TLR4-dependent adjuvant G3D6A, N. brasiliensis infection impaired selectively the induction of splenic antigen-specific Th1 but not of Th17 cells. Inhibition of MINCLE-dependent Th1/Th17 responses in mice infected with N. brasiliensis was dependent on IL-4/IL-13. Thus, helminth infection attenuated the Th17 response to MINCLE-dependent immunization in an organ- and adjuvant-specific manner via the Th2 cytokines IL-4/IL-13. Taken together, our results demonstrate downregulation of MINCLE expression on monocytes and macrophages by IL-4 as a possible mechanism of thwarted Th17 vaccination responses by underlying helminth infection. [ABSTRACT FROM AUTHOR] |
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