Helminthic glutamate dehydrogenase-dependent PGE2 production in monocyte and microglia potentiates Treg development with distinct transcriptional and epigenetic profiles

Abstract text

Introduction: Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. In neurocysticercosis (NCC), an inflammatory and clinically pleomorphic disease of the human brain, and most common cause of epilepsy in endemic regions, the disease severity strongly depends on the viability of the larval cyst of the pork tapeworm T. solium. Whereas dead cysts are often associated with epileptic manifestations, viable cysts in the brain mostly remain clinically silent by yet unknown mechanisms, potentially involving regulatory T cells (Tregs) in controlling inflammation.

Objective: In this work, we aim to uncover the underlying mechanisms for this dichotomy, especially the nature of cyst products and mechanisms controlling the development of Tregs during asymptomatic NCC and inflammation during symptomatic NCC.

Materials and Methods: Peripheral and brain immune cells from mice and healthy volunteers were pulsed with parasite viable, decaying cyst materials and the recombinant expressed cyst enzyme glutamate dehydrogenase GDH. Immune modulation and underlying mechanistic aspects were identified via adoptive transfer of cyst-treated DCs, and qPCR/FACS surrogate markers expression associated with LC/MS/MS profiling of eicosanoids and precursors and PGE2/IL-10 receptors antagonists. The mechanisms underlying Treg development and epigenetic landscape and transcriptional signatures associated with GDH-PGE2/IL-10-induced Tregs as well as FACS-sorted Tregs from NCC infected and healthy individuals were addressed via sequencing (ATACSeq, RNASeq).

Results: We demonstrated that the enzyme GDH from parasite viable cyst instructs tolerogenic CD206⁺ monocytes and Iba-1^lo microglia to release IL-10 and the lipid mediator PGE2. These act in concert via their respective receptors, converting naive CD4⁺ T cells into brain homing CD25^hiFoxP3⁺CTLA-4⁺CCR6⁺CCR7⁺ Tregs with distinct transcriptional signatures (e.g. JAK-STAT pathway) as identified in asymptomatic NCC patients. Moreover, while viable cyst strongly upregulated IL-10 and PGE2 transcription in microglia leading to Treg development, dead cyst material lacking GDH enzyme induced proinflammatory non-phagocytic microglia and TGF-β as potential drivers of epilepsy.

Conclusion: Harnessing the GDH-PGE2-IL-10 axis and targeting TGF-ß signaling may offer an important therapeutic strategy in inflammatory epilepsy and NCC.