Single-cell and spatial transcriptomics reveal aberrant lymphoid developmental programs driving granuloma formation

Krausgruber, Thomas; Redl, Anna; Barreca, Daniele; Doberer, Konstantin; Romanovskaia, Daria; Guarini, Maria; Unterluggauer, Luisa; Kleißl, Lisa; Atzmüller, Denise; Mayerhofer, Carolina; Kopf, Aglaja; Saluzzo, Simona; Lim, Clarice X.; Rexie, Praveen; Weichhart, Thomas; Bock, Christoph; Stary, Georg

doi:10.1016/j.immuni.2023.01.014

Cited by 40 publications

(27 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Enrichment of HLA-A , HLA - B , and HLA - C in “immune-interacting fibroblasts” was recently reported among sarcoidosis granulomas ( 71 ). Because of the specificity of these molecules for CD8 + T cells, our results together with the latter study emphasize the importance of CD8 + T cells in severe sarcoidosis.…”

Section: Discussionmentioning

confidence: 88%

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

Celada,

Lim,

Carisey

et al. 2023

Sci. Transl. Med.

View full text Add to dashboard Cite

Sarcoidosis is an interstitial lung disease (ILD) characterized by interferon-γ (IFN-γ) and T-box expressed in T cells (TBET) dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we found that pharmacological inhibition of phosphorylated SH2-containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFN-γ abundance, decreased large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8 + T cells. Mechanistically, we identified a posttranslational modification pathway in which the E3 F-box protein S-phase kinase–associated protein 2 (SKP2) targets TBET for ubiquitination in T cells under normal conditions. However, this pathway was disrupted by aberrant pSHP2 signaling in CD8 + T cells from patients with progressive pulmonary sarcoidosis and end-stage disease. Ex vivo inhibition of pSHP2 in CD8 + T cells from patients with end-stage sarcoidosis enhanced TBET ubiquitination and suppressed IFN-γ and collagen synthesis. Therefore, these studies provided new mechanistic insights into the SHP2-dependent posttranslational regulation of TBET and identified SHP2 inhibition as a potential therapeutic intervention against severe sarcoidosis. Furthermore, these studies also suggest that the small-molecule SHP2 inhibitor SHP099 might be used as a therapeutic measure against human diseases linked to TBET or ubiquitination.

show abstract

Section: Discussionmentioning

confidence: 88%

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

Celada,

Lim,

Carisey

et al. 2023

Sci. Transl. Med.

View full text Add to dashboard Cite

show abstract

“…34,35 Additionally, there is evidence of ECM-remodeling gene expression in granuloma-associated macrophages across diverse tissues, suggesting a potential localization of these macrophages within the ileal granulomas of Tnf ΔΑRE mice. 18 Consequently, IL-6 ligand production may play a role in the formation and function of these macrophage structures during ileal inflammation.…”

Section: Discussionmentioning

confidence: 99%

Cellular complexity and crosstalk in murine TNF-dependent ileitis: Different fibroblast subsets propel spatially defined ileal inflammation through TNFR1 signalling

Iliopoulou,

Tzaferis,

Prados

et al. 2023

Preprint

View full text Add to dashboard Cite

Crohn’s disease represents a persistent inflammatory disorder primarily affecting the terminal ileum. Through the application of single-cell RNA sequencing, we unveil the intricate cellular complexities within murine TNF-dependent ileitis, developing inTnfΔAREmice. Detailed immune cell analysis highlights B cell expansion, T cell effector reprogramming, and macrophage lineage shifts during inflammation. Focusing on stromal cells, we reveal a strong pro-inflammatory character, acquired by all fibroblast subsets, which exhibit complex communication patterns with the infiltrating immune and surrounding stromal cells. Interestingly, we identify thatTnfΔARE-induced ileitis is initiated in the lamina propria via TNFR1 pathway activation in villus-associated fibroblasts (Telocytes and Pdgfralowcells). Furthermore, we unveil separate spatial subsets of fibroblasts acting as exclusive responders to TNF, each orchestrating inflammation in different intestinal layers. Additionally, manipulating theTnfrsf1agene exclusively in fibroblast subsets suggests that inflammation is initiated by telocytes and Pdgfralowcells, while trophocytes drive its progression. This introduces novel evidence of spatial regulation of inflammation by fibroblast subsets, inciting and advancing disease in different layers of the gut. These findings underscore the pivotal role of fibroblasts in the inception and advancement of ileitis, proposing that targeting different fibroblast populations could impede the disease development and chronicity of inflammation.

show abstract

“…Dies resultierte in wissenschaftlichen Beiträgen zur phänotypischen und funktionellen Charakterisierung von gewebsständigen Gedächtnis‐T‐Zellen der Haut, 6 und deren Beteiligung an der (Immun)‐Pathogenese der Graft‐vs‐host‐Erkrankung, 7–9 und der HIV‐Krankheit 10 . Außerdem konnten wir Gedächtnis‐NK‐Zellen der Leber und im Kontaktekzem beschreiben, 11 den Effekt von Zeckenstichen auf das Immunsystem der Haut darstellen, 12 und den Aufbau von Hautgranulomen mit neuesten Methoden untersuchen 13 …”

Section: Abbildungunclassified

“…10 Außerdem konnten wir Gedächtnis-NK-Zellen der Leber und im Kontaktekzem beschreiben, 11 den Effekt von Zeckenstichen auf das Immunsystem der Haut darstellen, 12 und den Aufbau von Hautgranulomen mit neuesten Methoden untersuchen. 13 Dies hatte verschiedene Auszeichnungen zur Folge, wie zum Beispiel die Verleihung des Oskar-Gans Preises der Deutschen Dermatologischen Gesellschaft. In weiterer Folge wurde ich zum Forschungsdirektor der Klinik für Dermatologie der Medizinischen Universität Wien ernannt und zum Adjunct Principal Investigator am Zentrum für molekulare Medizin (CeMM) der Österreichischen Akade- Der Ferdinand von Hebra-Preis ist die renommierteste Auszeichnung der ÖGDV.…”

unclassified

Single-cell and spatial transcriptomics reveal aberrant lymphoid developmental programs driving granuloma formation

Cited by 40 publications

References 106 publications

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

Cellular complexity and crosstalk in murine TNF-dependent ileitis: Different fibroblast subsets propel spatially defined ileal inflammation through TNFR1 signalling

Ferdinand von Hebra‐Preis der ÖGDV 2022 für Georg Stary – die Haut als Modellorgan für translationale Forschung

Contact Info

Product

Resources

About

Single-cell and spatial transcriptomics reveal aberrant lymphoid developmental programs driving granuloma formation

Cited by 40 publications

References 106 publications

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 + T cells

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 + T cells

Cellular complexity and crosstalk in murine TNF-dependent ileitis: Different fibroblast subsets propel spatially defined ileal inflammation through TNFR1 signalling

Ferdinand von Hebra‐Preis der ÖGDV 2022 für Georg Stary – die Haut als Modellorgan für translationale Forschung

Contact Info

Product

Resources

About

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells

SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 ⁺ T cells