TY - JOUR
T1 - Targeting TREM2 signaling shows limited impact on cerebrovascular calcification
AU - Sridhar, Sucheta
AU - Zhou, Yingyue
AU - Ibrahim, Adiljan
AU - Bertazzo, Sergio
AU - Wyss, Tania
AU - Swain, Amanda
AU - Maheshwari, Upasana
AU - Huang, Sheng Fu
AU - Colonna, Marco
AU - Keller, Annika
N1 - Publisher Copyright:
© 2024 Sridhar et al.
PY - 2025/1
Y1 - 2025/1
N2 - Brain calcification, the ectopic mineral deposits of calcium phos-phate, is a frequent radiological finding and a diagnostic criterion for primary familial brain calcification. We previously showed that microglia curtail the growth of small vessel calcification via the triggering receptor expressed in myeloid 2 (TREM2) in the Pdgfbret/ret mouse model of primary familial brain calcification. Because boosting TREM2 function using activating antibodies has been shown to be beneficial in other disease conditions by aiding in microglial clearance of diverse pathologies, we investigated whether administration of a TREM2-activating antibody could mitigate vascular calcification in Pdgfbret/ret mice. Single-nucleus RNA-sequencing analysis showed that calcification-associated microglia share transcriptional similarities to disease-associated microglia and exhibited activated TREM2 and TGFβ signaling. Administration of a TREM2-activating antibody increased TREM2-dependent microglial deposition of cathepsin K, a collagen-degrading protease, onto calcifications. However, this did not ameliorate the calcification load or alter the mineral composition and the microglial phenotype around calcification. We therefore conclude that targeting microglia with TREM2 agonistic antibodies is insufficient to demineralize and clear vascular calcifications.
AB - Brain calcification, the ectopic mineral deposits of calcium phos-phate, is a frequent radiological finding and a diagnostic criterion for primary familial brain calcification. We previously showed that microglia curtail the growth of small vessel calcification via the triggering receptor expressed in myeloid 2 (TREM2) in the Pdgfbret/ret mouse model of primary familial brain calcification. Because boosting TREM2 function using activating antibodies has been shown to be beneficial in other disease conditions by aiding in microglial clearance of diverse pathologies, we investigated whether administration of a TREM2-activating antibody could mitigate vascular calcification in Pdgfbret/ret mice. Single-nucleus RNA-sequencing analysis showed that calcification-associated microglia share transcriptional similarities to disease-associated microglia and exhibited activated TREM2 and TGFβ signaling. Administration of a TREM2-activating antibody increased TREM2-dependent microglial deposition of cathepsin K, a collagen-degrading protease, onto calcifications. However, this did not ameliorate the calcification load or alter the mineral composition and the microglial phenotype around calcification. We therefore conclude that targeting microglia with TREM2 agonistic antibodies is insufficient to demineralize and clear vascular calcifications.
UR - http://www.scopus.com/inward/record.url?scp=85208082167&partnerID=8YFLogxK
U2 - 10.26508/lsa.202402796
DO - 10.26508/lsa.202402796
M3 - Article
C2 - 39467636
AN - SCOPUS:85208082167
SN - 2575-1077
VL - 8
JO - Life Science Alliance
JF - Life Science Alliance
IS - 1
M1 - e202402796
ER -