CCR2 Inhibition as a Dual-Target Strategy for Immune Modulation and HSCs preservation post-Irradiation
Presenter Status
Medical Student
Abstract Type
Translational Research
Primary Mentor or Principal Investigator
John Perry, PhD
Presentation Type
Poster
Start Date
21-5-2026 12:00 PM
End Date
21-5-2026 1:00 PM
Abstract Text
Background: Radiation-induced chronic inflammation exacerbates tissue damage and may lead to delayed effects of acute radiation exposure (DEARE), including bone marrow failure and hematologic malignancies. The recovery and long-term effects post-lethal ionizing radiation exposure are dependent on hematopoietic responses. Unfortunately, available approved radiation exposure drugs and bone marrow transplant have shown little to no benefit in mitigating bone marrow DEARE. With the increasing use of nuclear technology and threats of nuclear attacks, there is a rising need for developing medical countermeasures that can prevent DEARE, particularly hematological dysfunction. Given the CCL2/CCR2 axis as an essential mediator of inflammatory responses post, our research has focused on investigating small-molecule inhibitors of this axis as a medical countermeasure to mitigate DEARE.
Objectives/Goal: We aim to investigate the role of CCR2 modulation in mitigating inflammatory responses and the effects of inhibitors on hematopoietic stem and progenitor cells (HSPCs). The goal of our study is to mitigate DEARE by modulating inflammatory responses and preserving HSPCs functionality.
Methods/Design: Immune competent C57B6/J mice were irradiated with 7.5Gy and 12Gy partial body irradiation with 2.5% hind leg shielding. The mice were injected intraperitoneally with 7.5 mg/kg of CCR2 inhibitor (CCR2i) at 24 hours and 48 hours post-irradiation. Bone marrow, spleen, and peripheral blood tissues were collected 14 days post-radiation exposure. For the in vitro experiments, bone marrow-derived mononuclear cells were plated in 96-well plates, treated with 1mg/mL of a CCR2 inhibitor (CCR2i) following 1Gy radiation exposure, then cultured for 11 days. Flow cytometry using hematopoietic stem cells and progenitors, and myeloid markers, was used to analyze the samples.
Results: The CCR2 inhibitor treatment post-radiation exposure increased the frequency of short-term (ST_HSCs) and multipotent progenitor (MPP_HSCs) HSCs in the bone marrow and spleen. CCR2i treatment also promoted increased tissue-healing-associated M2-like anti-inflammatory monocytes in the spleen and bone marrow at day 14. In in vitro experiments, post-irradiation CCR2i treatment in HSC cultures also increased HSPCs compared to untreated controls.
Conclusions: These findings suggest that CCR2i could be beneficial in preventing depletion of HSPCs and promoting an increase of anti-inflammatory monocytes associated with patrolling and tissue healing to support post-irradiation recovery. Following these findings, the next step for this study is to determine whether CCR2 inhibition prevents pathological HSPC damage by conducting functional assays. We shall also investigate whether our CCR2i promotes macrophage polarization towards the tissue-protective M2 phenotype.
CCR2 Inhibition as a Dual-Target Strategy for Immune Modulation and HSCs preservation post-Irradiation
Background: Radiation-induced chronic inflammation exacerbates tissue damage and may lead to delayed effects of acute radiation exposure (DEARE), including bone marrow failure and hematologic malignancies. The recovery and long-term effects post-lethal ionizing radiation exposure are dependent on hematopoietic responses. Unfortunately, available approved radiation exposure drugs and bone marrow transplant have shown little to no benefit in mitigating bone marrow DEARE. With the increasing use of nuclear technology and threats of nuclear attacks, there is a rising need for developing medical countermeasures that can prevent DEARE, particularly hematological dysfunction. Given the CCL2/CCR2 axis as an essential mediator of inflammatory responses post, our research has focused on investigating small-molecule inhibitors of this axis as a medical countermeasure to mitigate DEARE.
Objectives/Goal: We aim to investigate the role of CCR2 modulation in mitigating inflammatory responses and the effects of inhibitors on hematopoietic stem and progenitor cells (HSPCs). The goal of our study is to mitigate DEARE by modulating inflammatory responses and preserving HSPCs functionality.
Methods/Design: Immune competent C57B6/J mice were irradiated with 7.5Gy and 12Gy partial body irradiation with 2.5% hind leg shielding. The mice were injected intraperitoneally with 7.5 mg/kg of CCR2 inhibitor (CCR2i) at 24 hours and 48 hours post-irradiation. Bone marrow, spleen, and peripheral blood tissues were collected 14 days post-radiation exposure. For the in vitro experiments, bone marrow-derived mononuclear cells were plated in 96-well plates, treated with 1mg/mL of a CCR2 inhibitor (CCR2i) following 1Gy radiation exposure, then cultured for 11 days. Flow cytometry using hematopoietic stem cells and progenitors, and myeloid markers, was used to analyze the samples.
Results: The CCR2 inhibitor treatment post-radiation exposure increased the frequency of short-term (ST_HSCs) and multipotent progenitor (MPP_HSCs) HSCs in the bone marrow and spleen. CCR2i treatment also promoted increased tissue-healing-associated M2-like anti-inflammatory monocytes in the spleen and bone marrow at day 14. In in vitro experiments, post-irradiation CCR2i treatment in HSC cultures also increased HSPCs compared to untreated controls.
Conclusions: These findings suggest that CCR2i could be beneficial in preventing depletion of HSPCs and promoting an increase of anti-inflammatory monocytes associated with patrolling and tissue healing to support post-irradiation recovery. Following these findings, the next step for this study is to determine whether CCR2 inhibition prevents pathological HSPC damage by conducting functional assays. We shall also investigate whether our CCR2i promotes macrophage polarization towards the tissue-protective M2 phenotype.
Comments
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Poster Board Number: 37