Marco Orecchioni, PhD

We are an international, multidisciplinary team fascinated by an unexpected discovery: macrophages and monocytes carry functional Olfactory Receptors (ORs), the largest family of Gprotein–coupled receptors (GPCRs), the same receptor family that lets us smell.

These immune “noses” detect dietderived aldehydes, oxidativestress byproducts, microbial metabolites, and even tumor volatiles compounds, rewiring inflammation that drives atherosclerosis, metabolic disorders, sepsis and cancer. By pairing cutting-edge single-cell ‘omics with invivo models and cellular and molecular biology, we aim to translate chemosensory immunology into first-in-class GPCR-based therapeutics.

Assistant Professor
Immunology Center of Georgia

Contact Us

Immunology Center of Georgia

1410 Laney Walker Blvd, CN 4092

706-729-2204

morecchioni@augusta.edu

What We Do

A central goal of the Orecchioni Lab is to uncover how olfactory receptors modulate innateimmune behavior in disease, and to translate these insights into therapeutic strategies. We integrate CRISPR-engineered reporter mice, high-dimensional flow cytometry, CyTOF, “omics” technologies, and invivo and in vitro assays and imaging to follow OR-expressing monocytes and macrophages from blood to tissue and to chart the signaling, metabolic, and transcriptional programs they modulate.

Four projects illustrate our approach:

Project 1 | OxidizedLDL sensing in atherosclerosis.
Inflammatory cues (LPS, oxLDL) upregulate Olfr2/OR6A2 on monocytes and macrophages. Olfr2 detects the lipidperoxidation aldehyde octanal, triggers NLRP3 inflammasome activation, and fuels IL1β release. Using conditional knockouts, pharmacologic antagonists, and competitive adoptive transfer, we test whether Olfr2 orchestrates monocyte homing, lipid accumulation, and formation of proinflammatory foamy macrophages that accelerate plaque progression.

Project 3 | Olfr2 signaling and function in melanoma immunity.
Melanoma tumors release octanal and other metabolites that activate Olfr2 on tumor-infiltrating monocytes/macrophages. Singlecell RNAseq, CyTOF, and spectral flow cytometry reveal that this axis boosts macrophage inflammasome activity and enhances CD8⁺ Tcell priming, correlating with better checkpointblockade responses. A new myeloid-specific Olfr2 knockout dissects how OR activation reshapes the tumor microenvironment and tests smallmolecule agonists as adjuvants to immunotherapy.

Project 2 | Octanal, oxidative stress, and sepsis.
We are studying whether endothelial dysfunction liberates octanal during oxidative stress. We study how circulating octanal engages Olfr2 on monocytes, promotes chemotaxis and extravasation, and amplifies the cytokine storm that underlies multi-organ failure in sepsis. Parallel metabolomic and lipidperoxidation assays define the enzymes that produce and the pathways that detoxify octanal, pointing to new biomarkers and drug targets.

Project 4 | Human translation & discovery of new immune ORs.
We are directly translating murine Olfr2 biology to its human ortholog, OR6A2, validating receptor expression, signaling, and ligand profiles in primary human monocytes/macrophages and carotidplaque specimens. In parallel, ligand-screening and single-cell multi-omics screens are uncovering previously unrecognized functional ORs in human and mouse innate immune cells, expanding the repertoire of chemosensory GPCRs we can target across cardiovascular, metabolic, and oncologic diseases.