TY - JOUR
T1 - PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis
AU - Chaney, Aisling M.
AU - Cropper, Haley C.
AU - Jain, Poorva
AU - Wilson, Edward
AU - Simonetta, Federico
AU - Johnson, Emily M.
AU - Alam, Israt S.
AU - Patterson, Ian T.J.
AU - Swarovski, Michelle
AU - Stevens, Marc Y.
AU - Wang, Qian
AU - Azevedo, Carmen
AU - Nagy, Sydney C.
AU - Benitez, Javier Ramos
AU - Deal, Emily M.
AU - Vogel, Hannes
AU - Andreasson, Katrin I.
AU - James, Michelle L.
N1 - Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved;
PY - 2023/6/28
Y1 - 2023/6/28
N2 - Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the 64Cu-radiolabeled TREM1 antibody–based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)–PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1+ cells in clinical brain biopsy samples from two treatment-naïve patients with MS but not in healthy control brain tissue. Thus, TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment.
AB - Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the 64Cu-radiolabeled TREM1 antibody–based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)–PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1+ cells in clinical brain biopsy samples from two treatment-naïve patients with MS but not in healthy control brain tissue. Thus, TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment.
UR - http://www.scopus.com/inward/record.url?scp=85163700495&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abm6267
DO - 10.1126/scitranslmed.abm6267
M3 - Article
C2 - 37379371
AN - SCOPUS:85163700495
SN - 1946-6234
VL - 15
JO - Science translational medicine
JF - Science translational medicine
IS - 702
M1 - eabm6267
ER -