Targeting stage specific influxed monocytes to treat acute and chronic back pain

University Of Virginia, Charlottesville VA

Investigators

Abstract

Targeting stage specific influxed monocytes to treat acute and chronic back pain Back pain is the most common contributor to lost workdays, with intervertebral disc herniation being a leading contributor. The pathogenesis of disc herniation and associated pain involves complex immune responses in which monocytes play key roles. Monocyte-specific C-C motif chemokine receptor 2 (CCR2) is critical for their recruitment to inflammatory tissues. Using transgenic mice for monocyte fate mapping, we detected a continuous influx of monocytes at disc hernia sites. Early CCR2 antagonist treatments markedly reduced total monocytes and macrophages at these sites and attenuated acute pain, whereas later treatments reduced subsequent monocytic influx with little impact on already infiltrated macrophages. However, it remains unclear how infiltrated monocytes respond to the local microenvironment and contribute to either the recovery or deterioration of disc herniation and associated pain. We hypothesize that blocking early infiltrating monocytes may alleviate acute inflammation but may lead to chronic inflammation due to inadequate initial inflammatory response and residual disc tissue. In contrast, inhibiting late-infiltrating monocytes mitigates chronic inflammation and augments the tissue repair function of early infiltrated monocytes-derived macrophages in disc herniation. The goal of this study is to determine the fates and functions of CCR2 monocytes in response to the specific microenvironment at the hernia site, aligning with our long-term goal to identify disease-modifying therapies. We will use a highly innovative inducible transgenic mouse strain to trace monocytes at various stages (Aim 1). We will distinguish the roles of the early and late influxes of monocytes by administering a clinically tested CCR2 antagonist (Aim 2). Additionally, we will elucidate and validate differences in human specimens taken at acute and chronic stages and establish correlations between signature effectors and clinical manifestations (Aim 3). Understanding of the immune responses at the molecular level will improve long-term outcomes by identifying biomarkers and target therapies.