Predictive screening of M1 and M2 macrophages reveals the immunomodulatory effectiveness of post spinal cord injury azithromycin treatment

Gensel, John C.; Kopper, Timothy J.; Zhang, Bei; Orr, Michael B.; Bailey, William M.

doi:10.1038/srep40144

Cited by 124 publications

(140 citation statements)

References 46 publications

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“…Azithromycin and other macrolide antibiotics are now being tested as immunomodulatory agents for CNS disorders. Specifically, we and others observed immunomodulatory effects and improved recovery with AZM treatment in spinal cord injury, stroke, and retinal ischemia/reperfusion injury . The neuroprotective properties of AZM in these models are associated with direct effects on macrophages .…”

Section: Introductionmentioning

confidence: 55%

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

et al. 2019

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Summary Introduction Azithromycin (AZM) and other macrolide antibiotics are applied as immunomodulatory treatments for CNS disorders. The immunomodulatory and antibiotic properties of AZM are purportedly independent. Aims To improve the efficacy and reduce antibiotic resistance risk of AZM‐based therapies, we evaluated the immunomodulatory and neuroprotective properties of novel AZM derivatives. We semisynthetically prepared derivatives by altering sugar moieties established as important for inhibiting bacterial protein synthesis. Bone marrow‐derived macrophages (BMDMs) were stimulated in vitro with proinflammatory, M1, stimuli (LPS + INF‐gamma) with and without derivative costimulation. Pro‐ and anti‐inflammatory cytokine production, IL‐12 and IL‐10, respectively, was quantified using ELISA. Neuron culture treatment with BMDM supernatant was used to assess derivative neuroprotective potential. Results Azithromycin and some derivatives increased IL‐10 and reduced IL‐12 production of M1 macrophages. IL‐10/IL‐12 cytokine shifts closely correlated with the ability of AZM and derivatives to mitigate macrophage neurotoxicity. Conclusions Sugar moieties that bind bacterial ribosomal complexes can be modified in a manner that retains AZM immunomodulation and neuroprotection. Since the effects of BMDMs in vitro are predictive of CNS macrophage responses, our results open new therapeutic avenues for managing maladaptive CNS inflammation and support utilization of IL‐10/12 cytokine profiles as indicators of macrophage polarization and neurotoxicity.

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Section: Introductionmentioning

confidence: 55%

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

et al. 2019

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“…Furthermore, inhibition of the IRE1 pathway through treatment with STF‐080310 prevented ER expansion and suppressed the M2 macrophage phenotype. This was observed in vitro through assessment of CD206 and arginase‐1, two strong markers used to characterize M2‐macrophage expression . Combined, the data presented suggest that therapeutic targeting of the IRE1 pathway or IL‐6 signaling may prevent the profibrotic activity of M2‐like macrophages in vivo .…”

Section: Introductionmentioning

confidence: 58%

IL‐6 mediates ER expansion during hyperpolarization of alternatively activated macrophages

et al. 2018

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Although recent evidence has shown that IL‐6 is involved in enhanced alternative activation of macrophages toward a profibrotic phenotype, the mechanisms leading to their increased secretory capacity are not fully understood. Here, we investigated the effect of IL‐6 on endoplasmic reticulum (ER) expansion and alternative activation of macrophages in vitro. An essential mediator in this ER expansion process is the IRE1 pathway, which possesses a kinase and endoribonuclease domain to cleave XBP1 into a spliced bioactive molecule. To investigate the IRE1‐XBP1 expansion pathway, IL‐4/IL‐13 and IL‐4/IL‐13/IL‐6‐mediated alternative programming of murine bone marrow‐derived and human THP1 macrophages were assessed by arginase activity in cell lysates, CD206 and arginase‐1 expression by flow cytometry, and secreted CCL18 by ELISA, respectively. Ultrastructural intracellular morphology and ER biogenesis were examined by transmission electron microscopy and immunofluorescence. Transcription profiling of 128 genes were assessed by NanoString and Pharmacological inhibition of the IRE1‐XBP1 arm was achieved using STF‐083010 and was verified by RT‐PCR. The addition of IL‐6 to the conventional alternative programming cocktail IL‐4/IL‐13 resulted in increased ER and mitochondrial expansion, profibrotic profiles and unfolded protein response‐mediated induction of molecular chaperones. IRE1‐XBP1 inhibition substantially reduced the IL‐6‐mediated hyperpolarization and normalized the above effects. In conclusion, the addition of IL‐6 enhances ER expansion and the profibrotic capacity of IL‐4/IL‐13‐mediated activation of macrophages. Therapeutic strategies targeting IL‐6 or the IRE1‐XBP1 axis may be beneficial to prevent the profibrotic capacity of macrophages.

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“…Thus, it is likely that MARCO can bind myelin lipids effectively. Although it has not been identified as a myelin receptor in SCI, we recently observed that macrophages upregulate MARCO in response to proinflammatory stimuli and express MARCO in the injured spinal cord (Gensel, Kopper, Zhang, Orr, & Bailey, ; Orr et al, ). MARCO activation, therefore, may be a potential mechanism for proinflammatory macrophage‐mediated myelin removal in SCI.…”

Section: Macrophage Receptor–mediated Myelin Removalmentioning

confidence: 99%

“…Similarly, it is well documented that macrophages increase IL‐12 release with myelin stimulation (Sun et al, ; Wang et al, ). Given that MARCO is present on macrophages after SCI (Gensel et al, ), it is possible that MARCO‐mediated myelin clearance may influence the M1‐like polarization observed in SCI. Conversely, SRAI/II has been implicated in the inhibition of IL‐12 production (Józefowski et al, ; Józefowski & Kobzik, ).…”

Section: Myelin–macrophage Interactionsmentioning

confidence: 99%

Myelin as an inflammatory mediator: Myelin interactions with complement, macrophages, and microglia in spinal cord injury

Kopper

Gensel

2017

J of Neuroscience Research

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Spinal cord injury (SCI) triggers chronic intraspinal inflammation consisting of activated resident and infiltrating immune cells (especially microglia/macrophages). The environmental factors contributing to this protracted inflammation are not well understood, however, myelin lipid debris is a hallmark of SCI. Myelin is also a potent macrophage stimuli and target of complement-mediated clearance and inflammation. The downstream effects of these neuro-immune interactions have the potential to contribute to ongoing pathology or facilitate repair. This depends in large part on whether myelin drives pathological or reparative macrophage activation states, commonly referred to as M1 (pro-inflammatory) or M2 (alternatively) macrophages respectively. Here we review the processes by which myelin debris may be cleared through macrophage surface receptors and the complement system, how this differentially influences macrophage and microglial activation states, and how the cellular functions of these myelin macrophages and complement proteins contribute to chronic inflammation and secondary injury after SCI.

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Predictive screening of M1 and M2 macrophages reveals the immunomodulatory effectiveness of post spinal cord injury azithromycin treatment

Cited by 124 publications

References 46 publications

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

IL‐6 mediates ER expansion during hyperpolarization of alternatively activated macrophages

Myelin as an inflammatory mediator: Myelin interactions with complement, macrophages, and microglia in spinal cord injury

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