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TLR2 in γδ T cells is required for metabolic support of IL-17A ocular mucosal immune response to a commensal bacterium [ATAC-seq]

ABSTRACT: The ocular surface is colonized by commensal microbiota, which tune the local mucosal immune response. However, the mechanisms underlying the induction of an IL-17 response by γδ T cells in response to ocular commensal bacteria, particularly Corynebacterium mastitidis (C. mast), have not been fully investigated. Here, we demonstrated that intrinsic TLR2 activation in γδ T cells by commensal microbiota is required for their IL-17A production and fatty acid oxidation. We also identified IκBζ, a transcription factor whose expression is upregulated by TLR2 signaling, as a key regulator to enhance the expression of genes responsible for IL-17A production and FAO program. This study highlights the role of TLR2-mediated transcriptional regulation in targeting effector cytokines and metabolic programs to support IL-17A responses to commensal bacteria.

ORGANISM(S): Mus musculus

PROVIDER: GSE236383 | GEO | 2024/05/15

REPOSITORIES: GEO

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Project description:Microglia are the resident mononuclear phagocytes of the CNS parenchyma and represent an initial line of defense against invading microorganisms. Microglia utilize Toll-like receptors (TLRs) for pathogen recognition and TLR2 specifically senses conserved motifs of gram-positive bacteria including lipoproteins, lipoteichoic acids, and peptidoglycan (PGN) leading to cytokine/chemokine production. Interestingly, primary microglia derived from TLR2 knockout (KO) mice over-expressed numerous IL-12 family members, including IL-12p40, IL-12p70, and IL-27 in response to intact S. aureus, but not the less structurally complex TLR2 ligands Pam3CSK4 or PGN. The ability of intact bacteria to augment IL-12 family member expression was specific for gram-positive organisms, since numerous gram-negative strains were unable to elicit exaggerated responses in TLR2 KO microglia. Inhibition of SYK or IRAK4 signaling did not impact heightened IL-12 family member production in S. aureus-treated TLR2 KO microglia, whereas PI3K, MAPK, and JNK inhibitors were all capable of restoring exaggerated cytokine expression to wild type levels. Additionally, elevated IL-12 production in TLR2 KO microglia was ablated by a TLR9 antagonist, suggesting that TLR9 drives IL-12 family member production following exposure to intact bacteria that remains unchecked in the absence of TLR2 signaling. Collectively, these findings indicate crosstalk between TLR2 and TLR9 pathways to regulate IL-12 family member production by microglia. The summation of TLR signals must be tightly controlled to ensure the timely cessation and/or fine tuning of cytokine signaling to avoid nonspecific bystander damage due to sustained IL-12 release. TLR2 KO mice were backcrossed with C57BL/6 animals for a minimum of eight generations prior to use in these studies. Age- and sex-matched C57BL/6 mice were used as wild type (WT) controls. Primary mixed glial cultures were prepared from the cerebral corticies of neonatal mice (2-4 days of age) and microglia were harvested using a differential shaking technique with a purity of >98%. A USA300 community-acquired methicillin-resistant S. aureus (CA-MRSA) clinical isolate recovered from a patient with a fatal brain abscess was used to stimulate the microglia isolates. Bacterial strains were heat-inactivated and used to stimulate microglia at 107 colony forming units (cfu)/well for 6 and 12 hours time points. Three replicates of each mouse type (WT, TLR2 KO) at both time points 6 and 12 hours were used for the microarray experiments. Data was only usable for 2 replicates of the KO-12 hr group.

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TLR2 in γδ T cells is required for metabolic support of IL-17A ocular mucosal immune response to a commensal bacterium [ATAC-seq]

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