PMID- 26597676 OWN - NLM STAT- MEDLINE DCOM- 20160912 LR - 20191023 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 12 DP - 2015 Nov 24 TI - Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injury. PG - 218 LID - 10.1186/s12974-015-0440-3 [doi] LID - 218 AB - BACKGROUND: Macrophages persist indefinitely at sites of spinal cord injury (SCI) and contribute to both pathological and reparative processes. While the alternative, anti-inflammatory (M2) phenotype is believed to promote cell protection, regeneration, and plasticity, pro-inflammatory (M1) macrophages persist after SCI and contribute to protracted cell and tissue loss. Thus, identifying non-invasive, clinically viable, pharmacological therapies for altering macrophage phenotype is a challenging, yet promising, approach for treating SCI. Azithromycin (AZM), a commonly used macrolide antibiotic, drives anti-inflammatory macrophage activation in rodent models of inflammation and in humans with cystic fibrosis. METHODS: We hypothesized that AZM treatment can alter the macrophage response to SCI and reduce progressive tissue pathology. To test this hypothesis, mice (C57BL/6J, 3-month-old) received daily doses of AZM (160 mg/kg) or vehicle treatment via oral gavage for 3 days prior and up to 7 days after a moderate-severe thoracic contusion SCI (75-kdyn force injury). Fluorescent-activated cell sorting was used in combination with real-time PCR (rtPCR) to evaluate the disposition and activation status of microglia, monocytes, and neutrophils, as well as macrophage phenotype in response to AZM treatment. An open-field locomotor rating scale (Basso Mouse Scale) and gridwalk task were used to determine the effects of AZM treatment on SCI recovery. Bone marrow-derived macrophages (BMDMs) were used to determine the effect of AZM treatment on macrophage phenotype in vitro. RESULTS: In accordance with our hypothesis, SCI mice exhibited significantly increased anti-inflammatory and decreased pro-inflammatory macrophage activation in response to AZM treatment. In addition, AZM treatment led to improved tissue sparing and recovery of gross and coordinated locomotor function. Furthermore, AZM treatment altered macrophage phenotype in vitro and lowered the neurotoxic potential of pro-inflammatory, M1 macrophages. CONCLUSIONS: Taken together, these data suggest that pharmacologically intervening with AZM can alter SCI macrophage polarization toward a beneficial phenotype that, in turn, may potentially limit secondary injury processes. Given that pro-inflammatory macrophage activation is a hallmark of many neurological pathologies and that AZM is non-invasive and clinically viable, these data highlight a novel approach for treating SCI and other maladaptive neuroinflammatory conditions. FAU - Zhang, Bei AU - Zhang B AD - Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA. bei.zhang@uky.edu. FAU - Bailey, William M AU - Bailey WM AD - Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA. william.bailey@uky.edu. FAU - Kopper, Timothy J AU - Kopper TJ AD - Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA. timothy.kopper@uky.edu. AD - Integrated Biological Sciences Graduate Program, College of Medicine, University of Kentucky, Lexington, KY, 40536, USA. timothy.kopper@uky.edu. FAU - Orr, Michael B AU - Orr MB AD - Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA. michael.orr1991@uky.edu. AD - Integrated Biological Sciences Graduate Program, College of Medicine, University of Kentucky, Lexington, KY, 40536, USA. michael.orr1991@uky.edu. FAU - Feola, David J AU - Feola DJ AD - Department of Pharmacy Practice and Science, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA. david.feola@uky.edu. FAU - Gensel, John C AU - Gensel JC AD - Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY, 40536, USA. gensel.1@uky.edu. AD - Spinal Cord and Brain Injury Research Center, University of Kentucky, B463 Biomed & Biological Science Research Building (BBSRB), 741 S. Limestone Street, Lexington, KY, 40536-0509, USA. gensel.1@uky.edu. LA - eng GR - P30 CA177558/CA/NCI NIH HHS/United States GR - P30 NS051220/NS/NINDS NIH HHS/United States GR - R01 AI095307/AI/NIAID NIH HHS/United States GR - NS051220 P30/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151124 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 83905-01-5 (Azithromycin) SB - IM MH - Animals MH - Azithromycin/pharmacology/*therapeutic use MH - Cell Line, Tumor MH - Cells, Cultured MH - Dose-Response Relationship, Drug MH - Female MH - Macrophages/*drug effects/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - Recovery of Function/*drug effects/physiology MH - Spinal Cord Injuries/*drug therapy/*metabolism PMC - PMC4657208 EDAT- 2015/11/26 06:00 MHDA- 2016/09/13 06:00 PMCR- 2015/11/24 CRDT- 2015/11/25 06:00 PHST- 2015/07/17 00:00 [received] PHST- 2015/11/18 00:00 [accepted] PHST- 2015/11/25 06:00 [entrez] PHST- 2015/11/26 06:00 [pubmed] PHST- 2016/09/13 06:00 [medline] PHST- 2015/11/24 00:00 [pmc-release] AID - 10.1186/s12974-015-0440-3 [pii] AID - 440 [pii] AID - 10.1186/s12974-015-0440-3 [doi] PST - epublish SO - J Neuroinflammation. 2015 Nov 24;12:218. doi: 10.1186/s12974-015-0440-3.