Macrophage metabolites controlling epithelial colon homeostasis
The aim of this sub-project is to understand how macrophage-secreted metabolites may act as general signals as well as nutrients for neighboring cells to maintain tissue function and control immune responses. We would like to characterize the global secretome of different macrophage populations and understand how they contribute to tissue and immune function in the intestine, and the liver. We are using different genetic models as well as organoids to understand their impact in colitis, colitis-associated cancer, liver regeneration, metabolic liver diseases, or the composition of the microbiome (together with C. Moissl-Eichinger, G. Schabbauer and M. Schweiger, O. Sharif, A. Miller) and colon organoids (G. Egger). We will investigate whether modulation of different enzymes that produce these metabolites in macrophages can have a beneficial effects during these diseases in a sex-specific manner (with G. Egger, A. Haschemi, G. Schabbauer, C. Moissl-Eichinger). We plan to deeply characterize the function of specific metabolites with potential novel nutritive and immunoregulatory functions. These metabolites or targeting their enzymes might be used to beneficially influence inflammatory disease.
Thomas Weichhart
Medical University of Vienna
Center for Pathobiochemistry & Genetics
Währingerstraße 10
1090 Vienna
thomas.weichhart@meduniwien.ac.at
Project Members
Connor Jankowski
Postdoc
SFB Member
Paul Ettel
MD-PhD Student
SFB Member
Alishan Sahu
PhD Student
SFB Member
Research Publications
Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling. Cai Z, Li W, Hager S, Wilson JL, Afjehi-Sadat L, Heiss EH, Weichhart T, Heffeter P, Weckwerth W. Cell Mol Immunol 2024 Feb 27. https://doi.org/10.1038/s41423-024-01134-0.
Aberrant Lipid Metabolism in Macrophages Is Associated with Granuloma Formation in Sarcoidosis. Lim CX, Redl A, Kleissl L, Pandey RV, Mayerhofer C, El Jammal T, Mazic M, Gonzales K, Sukhbaatar N, Krausgruber T, Bock C, Hengstschläger M, Calender A, Pacheco Y, Stary G, Weichhart T. Am J Respir Crit Care Med 2024 Feb 14. https://doi.org/10.1164/rccm.202307-1273OC.
Efficacy and safety of mTOR inhibition in cutaneous sarcoidosis: a single-centre trial. Redl A, Doberer K, Unterluggauer L, Kleissl L, Krall C, Mayerhofer C, Reininger B, Stary V, Zila N, Weninger W, Weichhart T, Bock C, Krausgruber T, Stary G. Lancet Rheumatol 2024 Feb;6(2):e81-e91. https://doi.org/10.1016/S2665-9913(23)00302-8.
Metabolic support by macrophages sustains colonic epithelial homeostasis. Fritsch SD, Sukhbaatar N, Gonzales K, Sahu A, Tran L, Vogel A, Mazic M, Wilson JL, Forisch S, Mayr H, Oberle R, Weiszmann J, Brenner M, Vanhoutte R, Hofmann M, Pirnes-Karhu S, Magnes C, Kühnast T, Weckwerth W, Bock C, Klavins K, Hengstschläger M, Moissl-Eichinger C, Schabbauer G, Egger G, Pirinen E, Verhelst SHL, Weichhart T. Cell Metabolism 2023 Sep 29:S1550-4131(23)00341-8. https://doi.org/10.1016/j.cmet.2023.09.010.
SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8+ T cells. Celada SI, Lim CX, Carisey AF, Ochsner SA, Arce Deza CF, Rexie P, Poli De Frias F, Cardenas-Castillo R, Polverino F, Hengstschläger M, Tsoyi K, McKenna NJ, Kheradmand F, Weichhart T, Rosas IO, Van Kaer L, Celada LJ. Sci Transl Med 2023 Sep 13;15(713):eade2581. https://doi.org/10.1126/scitranslmed.ade2581.
Duodenal macrophages control dietary iron absorption via local degradation of transferrin. Sukhbaatar N, Schöller M, Fritsch SD, Linke M, Horer S, Träger M, Mazic M, Forisch S, Gonzales K, Kahler JP, Binder C, Lassnig C, Strobl B, Mueller M, Scheiber-Mojdehkar B, Gundacker C, Dabsch S, Kain R, Hengstschläger M, Verhelst S, Weiss G, Theurl I, Weichhart T. Blood 2023 Apr 5:blood.2022016632. https://doi.org/10.1182/blood.2022016632.
Single-cell and spatial transcriptomics reveal aberrant lymphoid developmental programs driving granuloma formation. Krausgruber T, Redl A, Barreca D, Doberer K, Romanovskaia D, Dobnikar L, Guarini M, Unterluggauer L, Kleissl L, Atzmüller D, Mayerhofer C, Kopf A, Saluzzo S, Lim CX, Rexie P, Weichhart T, Bock C, Stary G. Immunity 2023 Feb 6:S1074-7613(23)00024-9. https://doi.org/10.1016/j.immuni.2023.01.014.
Leveraging macrophage metabolism for anticancer therapy: opportunities and pitfalls. Saha P, Ettel P, Weichhart T. Trends Pharmacol Sci 2024 Mar 16:S0165-6147(24)00045-2. https://doi.org/10.1016/j.tips.2024.02.005.
Not just sugar: Metabolic control of neutrophil development and effector functions. Ettel P, Weichhart T. J Leukoc Biol 2024 Mar 7:qiae057. https://doi.org/10.1093/jleuko/qiae057.
Tissue-resident macrophages - early passengers or drivers in the tumor niche? Vogel A, Weichhart T. Curr Opin Biotechnol 2023 Oct;83:102984.https://doi.org/10.1016/j.copbio.2023.102984.