•The co-culture model of mouse PBMC and RAW264.7 macrophages was established.•PBMC inhibit M1 phenotypic differentiation in RAW264.7 cells.•PBMC promote M2 phenotypic differentiation in RAW264.7 ...cells.•Macrophages boost the polarization of monocytes within PBMC into M2 macrophages.•STAT pathways are involved in the regulation of macrophages by PBMC.
Peripheral blood mononuclear cells (PBMC), sourced autologously, offer numerous advantages when procured: easier acquisition process, no in vitro amplification needed, decreased intervention and overall increased acceptability make PBMC an attractive candidate for cell therapy treatment. However, the exact mechanism by which PBMC treat diseases remains poorly understood. Immune imbalance is the pathological basis of many diseases, with macrophages playing a crucial role in this process. However, research on the role and mechanisms of PBMC in regulating macrophages remains scarce. This study employed an in vitro co-culture model of PBMC and RAW264.7 macrophages to explore the role and mechanisms of PBMC in regulating macrophages. The results showed that the co-culturing led to decreased expression of inflammatory cytokines and increased expression of anti-inflammatory cytokines in RAW264.7 or in the culture supernatant. Additionally, the pro-inflammatory, tissue matrix-degrading M1 macrophages decreased, while the anti-inflammatory, matrix-synthesizing, regenerative M2 macrophages increased in both RAW264.7 and monocytes within PBMC. Moreover, co-cultured macrophages exhibited a significantly decreased p-STAT1/STAT1 ratio, while the p-STAT6/STAT6 ratio significantly increased. This suggests that PBMC may inhibit M1 macrophage polarization by blocking STAT1 signaling cascades and may promote M2 macrophage polarization through the activation of STAT6 signaling cascades. Overall, this study sheds light on the role and mechanism of PBMC in regulating macrophages. Moreover, it was found that monocytes within co-cultured PBMC differentiated into M2 macrophages in the presence of macrophages. This finding provides experimental evidence for the use of PBMC in treating inflammatory diseases, especially macrophage-depleting inflammatory diseases such as osteoarthritis.
Reducing plaque lipid content and enhancing plaque stability without causing extensive apoptosis of foam cells are ideal requirements for developing a safe and effective treatment of atherosclerosis. ...In this study, we synthesized IR780-Gd-OPN nanomicelles by conjugating osteopontin (OPN) and loading a gadolinium-macrocyclic ligand (Gd-DOTA) onto near-infrared dye IR780-polyethylene glycol polymer. The nanomicelles were employed for mild phototherapy of atherosclerotic plaques and dual-mode imaging with near-infrared fluorescence and magnetic resonance. In vitro results reveal that the mild phototherapy mediated by IR780-Gd-OPN nanomicelles not only activates heat shock protein (HSP) 27 to protect foam cells against apoptosis but also inhibits the nuclear factor kappa-B (NF-κB) pathway to regulate lipid metabolism and macrophage polarization, thereby diminishing the inflammatory response. In vivo results further validate that mild phototherapy effectively reduces plaque lipid content and size while simultaneously enhancing plaque stability by regulating the ratio of M1 and M2-type macrophages. In summary, this study presents a promising approach for developing a safe and highly efficient method for the precise therapeutic visualization of atherosclerosis.
The rupture of unstable atherosclerotic plaques is a major cause of high mortality rates in cardiovascular diseases. Therefore, the ideal outcome of atherosclerosis treatment is to reduce plaque size while enhancing plaque stability. To address this challenge, we designed IR780-Gd-OPN nanomicelles for mild phototherapy of atherosclerosis. This treatment can effectively reduce plaque size while significantly improving plaque stability by increasing collagen fiber content and elevating the ratio of M2/M1 macrophages, which is mainly attributed to the inhibition of the NF-κB signaling pathway by mild phototherapy-activated HSP27. In summary, our proposed mild phototherapy strategy provides a promising approach for safe and effective treatment of atherosclerosis.
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Macrophage M1/M2 polarization Yunna, Chen; Mengru, Hu; Lei, Wang ...
European journal of pharmacology,
06/2020, Letnik:
877
Journal Article
Recenzirano
Macrophages can be affected by a variety of factors to change their phenotype and thus affect their function. Activated macrophages are usually divided into two categories, M1-like macrophages and ...M2-like macrophages. Both M1 macrophages and M2 macrophages are closely related to inflammatory responses, among which M1 macrophages are mainly involved in pro-inflammatory responses and M2 macrophages are mainly involved in anti-inflammatory responses. Improving the inflammatory environment by modulating the activation state of macrophages is an effective method for the treatment of diseases. In this review, we analyzed the mechanism of macrophage polarization from the tumor microenvironment, nanocarriers, nuclear receptor PPARγ, phagocytosis, NF-κB signaling pathways, and other pathways.
Lipopolysaccharide (LPS)-preconditioned mesenchymal stem cells (MSCs) possessed strong immunomodulatory and anti-inflammatory functions by secreting exosomes as major paracrine effectors. However, ...the specific effect of exosomes from LPS pre-MSCs (LPS pre-Exos) on peripheral nerve regeneration has yet to be documented. Here, we established a sciatic nerve injury model in rats and an inflammatory model in RAW264.7 cells to explore the potential mechanism between LPS pre-Exos and peripheral nerve repair. The local injection of LPS pre-Exos into the nerve injury site resulted in an accelerated functional recovery, axon regeneration and remyelination, and an enhanced M2 Macrophage polarization. Consistent with the data in vivo, LPS pre-Exos were able to shift the pro-inflammation macrophage into a pro-regeneration macrophage. Notably, TNF stimulated gene-6 (TSG-6) was found to be highly enriched in LPS pre-Exos. We obtained si TSG-6 Exo by the knockdown of TSG-6 in LPS pre-Exos to demonstrate the role of TSG-6 in macrophage polarization, and found that TSG-6 served as a critical mediator in LPS pre-Exos-induced regulatory effects through the inhibition of NF-ΚΒ and NOD-like receptor protein 3 (NLRP3). In conclusion, our findings suggested that LPS pre-Exos promoted macrophage polarization toward an M2 phenotype by shuttling TSG-6 to inactivate the NF-ΚΒ/NLRP3 signaling axis, and could provide a potential therapeutic avenue for peripheral nerve repair.
•LPS pre-Exos boost axon regeneration and SC remyelination via accelerating the M2 macrophage polarization after the PNI.•LPS pre-Exos induces M2 macrophages polarization via transferring TSG-6.•LPS pre-Exos skewed M2 macrophage polarization involved in the TSG-6/NF-KB/NLRP3 signaling pathway.
•Effects of macrophages on atherosclerosis are related to macrophage polarization.•Different macrophage phenotypes have different effects on the plaque progress.•Macrophage polarization is the ...potential targets for treating atherosclerosis.
Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.
Myocardial infarction (MI) is a serious cardiovascular disease with complex complications and high lethality. Currently, exosome (Exo) therapy has emerged as a promising treatment of ischemic MI due ...to its antioxidant, anti-inflammatory, and vascular abilities. However, traditional Exo delivery lacks spatiotemporal precision and targeting of microenvironment modulation, making it difficult to localize the lesion site for sustained effects. In this study, an injectable oxidized hyaluronic acid-polylysine (OHA-PL) hydrogel was developed to conveniently load adipose-derived mesenchymal stem cell exosomes (ADSC-Exos) and improve their retention under physiological conditions. The OHA-PL@Exo hydrogel with high spatiotemporal precision is transplanted minimally invasively into the ischemic myocardium to scavenge intracellular and extracellular reactive oxygen species, regulate macrophage polarization, and attenuate inflammation in the early phase of MI. In addition, this synergistic microenvironment modulation can effectively reduce myocardial fibrosis and ventricular remodeling, promote angiogenesis, and restore electrophysiological function in the late stage of MI. Therefore, this hyaluronic acid-polylysine to deliver exosomes has become a promising therapeutic strategy for myocardial repair.
•OHA-PL hydrogel, based on dynamic covalent cross-linking, exhibited excellent injectability, self-healing capabilities, biocompatibility.•OHA-PL hydrogel could serve as a promising vehicle platform.•OHA-PL@Exo hydrogel exhibited exceptional spatiotemporal precision.•OHA-PL@Exo hydrogel scavenged ROS, regulated macrophage polarization, and sattenuated inflammation.•The innovative approach holds great promise as a therapeutic strategy for myocardial repair.
•Tethering exosomes to CS-AT hydrogel generated multifunctional hydrogel.•Hydrogels are capable of storing biologics and stably delivering exosome.•Exosomes from hydrogel accelerated healing of ...diabetic wounds by angiogenesis.•Synergy of CS-AT and exosome effectively induced M2 macrophage polarization.
Developing multifunctional wound dressings capable of inducing rapid angiogenesis provides promise for diabetic wound healing, and triggering proper immune responses has been proposed as a potential way to facilitate angiogenesis. Here, we developed exosomes-laden injectable hydrogel with self-healing ability based on chitosan-graft-aniline tetramer (CS-AT) and dibenzaldehyde-terminated poly (ethylene glycol) (PEG-DA), which can enhance diabetic wound healing by stably releasing exosomes. In vivo, CS-AT hydrogel loaded with exosomes (CS-AT-Exo hydrogel) apparently accelerated the diabetic full-thickness wound healing, characterized by promoted wound healing efficiency, quick re-epithelization, favorable collagen deposition, and abundant angiogenesis at the wound beds. In addition, the synergistic effect of hydrogel and exosomes induced local regulation of M2 macrophages polarization. In vitro, CS-AT hydrogel and exosomes can synergistically promote the polarization of M2 macrophages in CS-AT-Exo hydrogel. Furthermore, the CS-AT-Exo hydrogel with coculture of macrophages significantly enhanced the ability of human umbilical vein endothelial cells (HUVECs) to proliferation, migration, and tube formation. These findings revealed important mechanisms by which multifunctional CS-AT-Exo hydrogels with continuous exosomes release can enhance angiogenesis and diabetic wound healing by synergistically inducing M2 macrophage polarization, suggesting a potential treatment strategy for diabetic wounds.
Extracellular vesicles (EVs) can regulate the polarization of macrophages in a variety of inflammatory diseases by mediating intercellular signal transduction and affecting the occurrence and ...development of diseases. After macrophages are regulated by EVs, they mainly show two phenotypes: the proinflammatory M1 type and the anti-inflammatory M2 type. A large number of studies have shown that in diseases such as mastitis, inflammatory bowel disease, Acute lung injury, and idiopathic pulmonary fibrosis, EVs promote the progression of the disease by inducing the M1-like polarization of macrophages. In diseases such as liver injury, asthma, and myocardial infarction, EVs can induce M2-like polarization of macrophages, inhibit the inflammatory response, and reduce the severity of the disease, thus indicating new pathways for treating inflammatory diseases. The EV/macrophage axis has become a potential target for inflammatory disease pathogenesis and comprehensive treatment. This article reviews the structure and function of the EV/macrophage axis and summarizes its biological functions in inflammatory diseases to provide insights for the diagnosis and treatment of inflammatory diseases.
Endothelial cell (EC)-derived signals contribute to organ regeneration, but angiocrine metabolic communication is not described. We found that EC-specific loss of the glycolytic regulator pfkfb3 ...reduced ischemic hindlimb revascularization and impaired muscle regeneration. This was caused by the reduced ability of macrophages to adopt a proangiogenic and proregenerative M2-like phenotype. Mechanistically, loss of pfkfb3 reduced lactate secretion by ECs and lowered lactate levels in the ischemic muscle. Addition of lactate to pfkfb3-deficient ECs restored M2-like polarization in an MCT1-dependent fashion. Lactate shuttling by ECs enabled macrophages to promote proliferation and fusion of muscle progenitors. Moreover, VEGF production by lactate-polarized macrophages was increased, resulting in a positive feedback loop that further stimulated angiogenesis. Finally, increasing lactate levels during ischemia rescued macrophage polarization and improved muscle reperfusion and regeneration, whereas macrophage-specific mct1 deletion prevented M2-like polarization. In summary, ECs exploit glycolysis for angiocrine lactate shuttling to steer muscle regeneration from ischemia.
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•Endothelial loss of pfkfb3 impairs ischemic muscle revascularization and regeneration•EC-derived lactate instructs MCT1-dependent macrophage functional polarization•Lactate-polarized macrophages promote muscle revascularization and regeneration•Restoring lactate levels improves macrophage polarization and recovery from ischemia
Endothelial cells (ECs) critically control muscle recovery from ischemia by secreting lactate. Angiocrine lactate is taken up and oxidized by macrophages in an MCT1-dependent fashion. Lactate-mediated macrophage polarization promotes revascularization and muscle regeneration. Consequently, EC-specific loss of pfkfb3 lowers muscle lactate levels and impairs muscle recovery from ischemia.
Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune ...rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ, chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in
studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a "continuum" of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.
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