TY - JOUR
T1 - Chemokine signaling mediated monocyte infiltration affects anxiety-like behavior following blast injury
AU - Murugan, Madhuvika
AU - Ravula, Arunreddy
AU - Gandhi, Ajay
AU - Vegunta, Geetasravya
AU - Mukkamalla, Sushni
AU - Mujib, Waleed
AU - Chandra, Namas
N1 - Funding Information:
This work was supported by New Jersey Commission on Brain Injury Research (CBIR16IRG017, CBIR17PIL020, CBIR20IRG011) and USAMRMC (W81XWH-15-1-0303). Eren Alay and Jose Rodriguez were involved in maintenance and running of the shock tube used for blast injuries. We thank Vijayalakshmi Santhakumar for sharing the electrophysiology equipment and resources. M.M. conceived and planned the experiments. M.M. A.R. A.G. G.V. W.M. and S.M. carried out the experiments. M.M. and N.C. contributed to the interpretation of the results. M.M. took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.
Funding Information:
This work was supported by New Jersey Commission on Brain Injury Research ( CBIR16IRG017 , CBIR17PIL020 , CBIR20IRG011 ) and USAMRMC (W81XWH-15-1-0303). Eren Alay and Jose Rodriguez were involved in maintenance and running of the shock tube used for blast injuries. We thank Vijayalakshmi Santhakumar for sharing the electrophysiology equipment and resources.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/8
Y1 - 2020/8
N2 - The activation of resident microglia and infiltrated monocytes are known potent mediators of chronic neuroinflammation following traumatic brain injury (TBI). In this study, we use a mouse model of blast-induced TBI (bTBI) to investigate whether microglia and monocytes contribute to the neuroinflammatory and behavioral consequences of bTBI. Eight-ten week old mice were subject to moderate TBI (180 kPa) in a shock tube. Using double transgenic CCR2RFP/+: CX3CR1GFP/+ mice, we were able to note that in addition to resident Cx3CR1+ microglia, infiltrating CCR2+ monocytes also contributed to the expanding macrophage population that was observed after bTBI. The microglia activation and monocyte infiltration occurred as early as 4 h and lasted up to 30d after blast exposure, suggesting chronic inflammation. The infiltration of monocytes may be partly mediated by chemokine CCL2-CCR2 signaling axis and compromised blood brain barrier permeability. Hence, bTBI-induced infiltration of monocytes and production of IL-1β were prevented in mice lacking CCR2 (CCR2 KO). Finally, this study showed that interference of monocyte infiltration using CCR2 KO, ameliorated the chronic effects of bTBI such as anxiety-like behavior and short-term memory decline. Taken together, these data suggest that bTBI leads to activation of both resident microglia and infiltrated monocytes. The infiltration of monocytes was partly mediated by CCL2-CCR2 signaling, which in turn contributes to increased production of IL-1β leading to behavioral deficits after bTBI. Furthermore, bTBI induced behavioral outcomes were reduced by targeting CCL2-CCR2 signaling, highlighting the significance of this signaling axis in bTBI pathology.
AB - The activation of resident microglia and infiltrated monocytes are known potent mediators of chronic neuroinflammation following traumatic brain injury (TBI). In this study, we use a mouse model of blast-induced TBI (bTBI) to investigate whether microglia and monocytes contribute to the neuroinflammatory and behavioral consequences of bTBI. Eight-ten week old mice were subject to moderate TBI (180 kPa) in a shock tube. Using double transgenic CCR2RFP/+: CX3CR1GFP/+ mice, we were able to note that in addition to resident Cx3CR1+ microglia, infiltrating CCR2+ monocytes also contributed to the expanding macrophage population that was observed after bTBI. The microglia activation and monocyte infiltration occurred as early as 4 h and lasted up to 30d after blast exposure, suggesting chronic inflammation. The infiltration of monocytes may be partly mediated by chemokine CCL2-CCR2 signaling axis and compromised blood brain barrier permeability. Hence, bTBI-induced infiltration of monocytes and production of IL-1β were prevented in mice lacking CCR2 (CCR2 KO). Finally, this study showed that interference of monocyte infiltration using CCR2 KO, ameliorated the chronic effects of bTBI such as anxiety-like behavior and short-term memory decline. Taken together, these data suggest that bTBI leads to activation of both resident microglia and infiltrated monocytes. The infiltration of monocytes was partly mediated by CCL2-CCR2 signaling, which in turn contributes to increased production of IL-1β leading to behavioral deficits after bTBI. Furthermore, bTBI induced behavioral outcomes were reduced by targeting CCL2-CCR2 signaling, highlighting the significance of this signaling axis in bTBI pathology.
KW - Blast
KW - Brain injury
KW - CCL2-CCR2 signaling
KW - Chemokine
KW - Microglia
KW - Monocyte infiltration
UR - http://www.scopus.com/inward/record.url?scp=85082848942&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082848942&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2020.03.029
DO - 10.1016/j.bbi.2020.03.029
M3 - Article
C2 - 32240765
AN - SCOPUS:85082848942
SN - 0889-1591
VL - 88
SP - 340
EP - 352
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -