Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury

Ma, Shanfeng; Chen, Yue-Juan; Zhang, Jingxing; Shen, Lin; Wang, Rui; Zhou, Jiansheng; Hu, Jianguo; Lü, He‐Zuo

doi:10.1016/j.bbi.2014.11.007

Cited by 152 publications

(135 citation statements)

References 57 publications

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“…Hepatic non-parenchymal cells were isolated and analyzed by flow cytometry for CD68, CD86, and CD163 expression. We combined these markers to define hepatic macrophage phenotypes as being classically (M1-like, CD68 [10,34]. We found that the proportion of M1-like hepatic macrophages significantly increased whereas the proportion of M2-like macrophages significantly decreased in fibrotic livers compared with healthy controls (Fig.…”

Section: Splenectomy Reverses the M1-dominant Hepatic Macrophage Phenmentioning

confidence: 93%

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The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis

Wei

et al. 2018

Cell Physiol Biochem

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Background/Aims: Liver fibrosis is a complex process of tissue remodeling in response to injury. Hepatic macrophages have been identified as a key player in this process. As the largest lymphoid organ in the body, the spleen exerts both local and systemic effects on immune cell response. Splenectomy can improve hepatic function during the treatment of liver cirrhosis. However, whether the spleen influences disease progression through the modulation of hepatic macrophages remains unclear. Methods: We examined ex vivo hepatic macrophage responses from splenectomized or sham operated rats and performed splenocyte adoptive transfer studies, in combination with in vivo CCL2 blockade, in splenectomized or sham operated rats. Results: We found that splenectomy reduced fibrosis severity and monocyte/ macrophage infiltration within the injured liver. Splenectomy also reduced secretion of the monocyte chemokine CCL2 by hepatic macrophages. Ex vivo, splenocytes, especially splenic macrophages, promoted CCL2 secretion via upregulation of SOCS3 signaling in hepatic macrophages. Migration of splenic monocytes in response to conditioned medium from hepatic macrophages was inhibited by the blockade of SOCS3–CCL2–CCR2 signaling. Splenectomy also attenuated the establishment of an M1-dominant hepatic macrophage phenotype whilst the adoptive transfer of splenocytes could partly reverse this effect and exacerbate fibrosis. However, CCL2 blockade following adoptive splenocyte transfer restored the protective effects of splenectomy. Conclusion: Our study demonstrates that splenic macrophages can promote hepatic macrophage secretion of CCL2, which in turn facilitates monocyte recruitment and the establishment of an M1-dominant hepatic macrophage phenotype, and thus increase the severity of liver fibrosis.

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Section: Splenectomy Reverses the M1-dominant Hepatic Macrophage Phenmentioning

confidence: 93%

“…The markers of M1 and M2 macrophages differ between species. In rat, CD68 is a pan marker of monocytes and macrophages and CD86 and CD163 have been widely used to classify M1-and M2-like macrophages respectively [9,10].…”

Section: Introductionmentioning

confidence: 99%

The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis

Wei

et al. 2018

Cell Physiol Biochem

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“…Alternatively activated MMΦ have increased phagocytic activity and provide neuroprotection by reducing production of inflammatory mediators and downregulating neurotoxic pathways (Hu et al, 2015). Adoptive transfer of alternatively activated macrophages improves functional recovery in spinal cord injury (Ma et al, 2015). This ultra-early alternative activation of resident microglia before the first wave of peripheral leukocyte infiltration (Hammond et al, 2012; Wang and Dore, 2007) suggests that microglia react quickly to ICH insult.…”

Section: Discussionmentioning

confidence: 99%

Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage

Chang

Wan

et al. 2017

Neurobiology of Disease

113

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Microglia/macrophages (MMΦ) are highly plastic phagocytes that can promote both injury and repair in diseased brain through the distinct function of classically activated and alternatively activated subsets. The role of MMΦ polarization in intracerebral hemorrhage (ICH) is unknown. Herein, we comprehensively characterized MMΦ dynamics after ICH in mice and evaluated the relevance of MMΦ polarity to hematoma resolution. MMΦ accumulated within the hematoma territory until at least 14 days after ICH induction. Microglia rapidly reacted to the hemorrhagic insult as early as 1–1.5 h after ICH and specifically presented a “protective” alternatively activated phenotype. Substantial numbers of activated microglia and newly recruited monocytes also assumed an early alternatively activated phenotype, but the phenotype gradually shifted to a mixed spectrum over time. Ultimately, markers of MMΦ classic activation dominated at the chronic stage of ICH. We enhanced MMΦ alternative activation by administering intraperitoneal injections of rosiglitazone, and subsequently observed elevations in CD206 expression on brain-isolated CD11b+ cells and increases in IL-10 levels in serum and perihematomal tissue. Enhancement of MMΦ alternative activation correlated with hematoma volume reduction and improvement in neurologic deficits. Intraventricular injection of alternative activation signature cytokine IL-10 accelerated hematoma resolution, whereas microglial phagocytic ability was abolished by IL-10 receptor neutralization. Our results suggest that MMΦ respond dynamically to brain hemorrhage by exhibiting diverse phenotypic changes at different stages of ICH. Alternative activation-skewed MMΦ aid in hematoma resolution, and IL-10 signaling might contribute to regulation of MMΦ phagocytosis and hematoma clearance in ICH.

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“…M1 macrophage polarization status is closely related to the pathogenesis of several inflammation-associated diseases, including periprosthetic osteolysis [38, 39], myocardial infarction [40], diabetes [41], and spinal cord injury [42]. Indeed, modulation of macrophage polarization to limit inflammation and induce tissue regeneration is emerging as promising treatment approach for these and other serious diseases [5, 43].…”

Section: Discussionmentioning

confidence: 99%

Establishment of NF-κB sensing and interleukin-4 secreting mesenchymal stromal cells as an “on-demand” drug delivery system to modulate inflammation

et al. 2017

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Chronic inflammation is associated with upregulation of the transcription factor NF-κB and excessive inflammatory cytokine secretion by M1 macrophages. The anti-inflammatory cytokine IL-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory and tissue regenerative M2 phenotype, thus reducing inflammation and enhancing tissue regeneration. We have generated NF-κB responsive, or constitutively active IL4-expression lentiviral vectors transduced into murine bone marrow-derived mesenchymal stromal cells (MSCs). MSCs with a constitutively active IL-4 expression vector produced large quantities of IL-4 continuously whereas IL-4 secretion was significantly induced by lipopolysaccharide (LPS) in the NF-κB sensing MSCs. In contrast, LPS had no effect on MSCs with IL-4 secretion driven by a constitutively active promoter. We also found that intermittent and continuous LPS treatment displayed distinct NF-κB activation profiles, and this regulation was independent of IL-4 signaling. The supernatant containing IL-4 from the LPS treated MSCs suppressed M1 marker (iNOS and TNFα) expression and enhanced M2 marker (Arginase 1, CD206, and IL1Ra) expression in primary murine macrophages. The IL-4 secretion at the basal, non-LPS induced level was sufficient to suppress TNFα and enhance Arginase 1 at a lower level, but had no significant effects on iNOS, CD206, and IL1Ra expression. Finally, IL-4 secretion at basal or LPS-induced levels significantly suppressed osteogenic differentiation of MSCs. Our findings suggest that the IL-4 secreting MSCs driven by NF-κB sensing or constitutive active promoter have great potential for mitigating the effects of chronic inflammation and promoting earlier tissue regeneration.

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Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury

Cited by 152 publications

References 57 publications

The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis

The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis

Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage

Establishment of NF-κB sensing and interleukin-4 secreting mesenchymal stromal cells as an “on-demand” drug delivery system to modulate inflammation

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