Abstract

PO122 - Itaconate Restrains Granuloma Formation by Modulating Macrophage Activation and Transformation

Cátia Rodrigues (Portugal)^{1 2}; Relber A. Gonçales (Portugal)^{1 2}; Marcela Oliveira (Portugal)^{1 2}; Diana Santos-Ribeiro (Portugal)^{1 2}; Rita Silva-Gomes (Portugal)^{1 2}; António Morais (Portugal)^{3 4}; Hélder Novais e Bastos (Portugal)^{3 4 5}; Cristina Cunha (Portugal)^{1 2}; Agostinho Carvalho (Portugal)^{1 2};

1 - Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal; 2 - ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal; 3 - Faculdade de Medicina da Universidade do Porto, Porto, Portugal; 4 - Centro Hospitalar Universitário de São João, EPE, Porto, Portugal; 5 - Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal;

Keywords: Acod1; Immunometabolism; Itaconate;

Select the theme: Genetics and Immunopathology: Advances in Contemporary Understanding and Prospects for Future Research
Type: Original Papers
Presentation: Poster Presentation

Introduction: Sarcoidosis is a multiorgan disease of unknown etiology characterized by non-caseating granulomas, predominantly in the lungs. While the histological landscape of sarcoid granulomas is well understood, the inflammatory mechanisms driving their formation and persistence remain unclear at the genetic, molecular and inflammatory level. The aconitate decarboxylase 1 (Acod1) gene encodes a highly responsive enzyme to pro-inflammatory stimuli that converts cis-aconitate, a tricarboxylic acid (TCA) cycle intermediate, to itaconate, a key regulator of inflammatory responses.

Objectives: To evaluate the immunometabolic role of itaconate in regulating granulomatous inflammation in sarcoidosis.

Materials and Methods: We exploited an in vivo mouse model of granuloma formation on WT and Acod1-/- mice. Furthermore, we established in vitro models of multinucleated giant cells (MGCs) from murine bone marrow precursors and peripheral blood cells from sarcoidosis patients, which were also used to model granulomatous-like aggregation in vitro.

Results: We identified itaconate as an important player in granuloma formation in vivo, as evidenced by the larger granuloma-like structures exhibited by Acod1-/- mice, an effect reversed upon itaconate treatment. Cells from Acod1-/- mice were shown to occupy a larger area within the granulomas, suggesting enhanced MGC formation and a more pronounced epithelial-like transition. Consistently, the IL-4/JAK/STAT6 signaling axis, associated with macrophage transformation, was activated during this process, but suppressed by itaconate in our experimental setting. Pharmacological blockade with ruxolitinib mitigated granulomatous inflammation in Acod1-/- mice by hindering the pathogenic activation of the IL-4/JAK/STAT6 axis. Finally, using PBMCs from sarcoidosis patients, we found that itaconate supplementation markedly reduced the size and number of granuloma-like structures and limited MGC formation, mirroring the murine findings.

Conclusions: Collectively, these findings emphasize a pivotal role for itaconate in granuloma formation in sarcoidosis and lay the foundation for a novel immunometabolic-based intervention for the management of patients with sarcoidosis.