Regulatory CD4+ T cells (Tregs) are critical for maintaining tolerance to self. Chronic inflammation can cause Treg instability which is defined by loss of CD25 and the lineage-defining transcription factor FOXP3, resulting in exTreg cells.
To better understand the factors driving Treg to exTreg conversion, we analyzed transcriptomes of Treg subsets expressing varied levels of CD25 and FOXP3 in human peripheral blood CD4+ T cells.
We found differential expression of genes related to inflammatory signaling (IFNG, TNF), cytotoxicity (PRF1, GZMB) and cellular stress (HSPA5). This was confirmed at the protein level by flow cytometry. Distinct Treg populations were also defined by unique metabolic profiles suggesting a role of cell-intrinsic metabolic programs in maintaining Treg stability.
Our findings start to define novel cellular pathways contributing to Treg homeostasis and instability in human peripheral blood.
We acknowledge the support from National Institutes of Health (awards P01 HL136275 and R35 HL145241) to K.L.
Lymphocyte Differentiation and Peripheral Maintenance (LYM)
Smriti Parashar, P. Roy, Mohammad Oliaeimotlagh et al.· Journal of Immunology· 0 citations
Olfactory receptors (ORs), the largest family of G protein—coupled receptors, are emerging regulators of innate immunity. While specific ORs, such as Olfr2, have been linked to vascular inflammation, the broader role of OR signaling in macrophage-driven atherogenesis remains unclear.
Aortic macrophages from atherosclerosis-prone Apoe-/- mice were profiled by bulk RNA-seq to identify expressed ORs. Olfr519, the receptor for 3-phenylpropylpropionate (3-PPP), a potential gut microbiota—derived metabolite, was identified and confirmed by flow cytometry in aortic and bone marrow—derived macrophages. The human ortholog OR10A3 was analyzed in plaque macrophages, monocyte-derived macrophages, and circulating monocytes following stimulation with LPS and 3-PPP. Spatial transcriptomics (COSMX SMI) examined OR10A3 expression relative to markers of inflammatory macrophages. Functional assays assessed calcium flux and cytokine secretion after 3-PPP exposure, and receptor dependence was tested by siRNA knockdown and genetic deletion. In vivo studies included administration of 3-PPP in Apoe-/- mice and bone marrow transplantation in Ldlr-/- recipients.
Olfr519 was significantly upregulated in aortic macrophages. 3-PPP stimulation induced rapid Ca²+ flux and strong IL-1β/IL-1α secretion, which were abolished by receptor knockdown or deletion. OR10A3 was expressed in human plaque macrophages and monocytes, upregulated by LPS and 3-PPP, and co-localized with IL1B and IL1A transcripts. OR10A3 silencing reduced 3-PPP—induced IL-1β release. In vivo, 3-PPP accelerated atherosclerosis in Apoe-/- mice, whereas Olfr519-deficient bone marrow reduced lesions in Ldlr-/- mice.
The here-identified macrophage-intrinsic Olfr519/OR10A3/3-PPP axis amplifies inflammasome-dependent cytokine release and promotes atherogenesis, defining a novel GPCR-mediated sensory pathway and a potential therapeutic target for vascular inflammation.
AHA CDA Award
Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
Marco Orecchioni, Adil Ijaz, Natalya Resto Trujillo et al.· Journal of Immunology· 0 citations
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