by Keyword: Macrophage

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Mesquida-Veny, Francina, Del Río, José Antonio, Hervera, Arnau, (2021). Macrophagic and microglial complexity after neuronal injury Progress in Neurobiology , 101970

Central nervous system (CNS) injuries do not heal properly in contrast to normal tissue repair, in which functional recovery typically occurs. The reason for this dichotomy in wound repair is explained in part by macrophage and microglial malfunction, affecting both the extrinsic and intrinsic barriers to appropriate axonal regeneration. In normal healing tissue, macrophages promote the repair of injured tissue by regulating transitions through different phases of the healing response. In contrast, inflammation dominates the outcome of CNS injury, often leading to secondary damage. Therefore, an understanding of the molecular mechanisms underlying this dichotomy is critical to advance in neuronal repair therapies. Recent studies highlight the plasticity and complexity of macrophages and microglia beyond the classical view of the M1/M2 polarization paradigm. This plasticity represents an in vivo continuous spectrum of phenotypes with overlapping functions and markers. Moreover, macrophage and microglial plasticity affect many events essential for neuronal regeneration after injury, such as myelin and cell debris clearance, inflammation, release of cytokines, and trophic factors, affecting both intrinsic neuronal properties and extracellular matrix deposition. Until recently, this complexity was overlooked in the translation of therapies modulating these responses for the treatment of neuronal injuries. However, recent studies have shed important light on the underlying molecular mechanisms of this complexity and its transitions and effects on regenerative events. Here we review the complexity of macrophages and microglia after neuronal injury and their roles in regeneration, as well as the underlying molecular mechanisms, and we discuss current challenges and future opportunities for treatment.

Keywords: Neuronal injury, Neuroinflammation, Macrophages, Microglia, Chemokines and cytokines, Regeneration

Cremonese, C., Schierwagen, R., Uschner, F. E., Torres, S., Tyc, O., Ortiz, C., Schulz, M., Queck, A., Kristiansen, G., Bader, M., Sauerbruch, T., Weiskirchen, R., Walther, T., Trebicka, J., Klein, S., (2020). Short-term western diet aggravates non-alcoholic fatty liver disease (NAFLD) with portal hypertension in TGR(mREN2)27 rats International Journal of Molecular Sciences 21, (9), 3308

Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.

Keywords: ADGRE1, EMR1, F4/80, Immunity, Liver fibrosis, Macrophage, NAFLD, Portal hypertension, TGR(mREN2)27, Western diet

Gouveia, Virgínia M., Rizzello, Loris, Nunes, Claudia, Poma, Alessandro, Ruiz-Perez, Lorena, Oliveira, António, Reis, Salette, Battaglia, Giuseppe, (2019). Macrophage targeting pH responsive polymersomes for glucocorticoid therapy Pharmaceutics 11, (11), 614

Glucocorticoid (GC) drugs are the cornerstone therapy used in the treatment of inflammatory diseases. Here, we report pH responsive poly(2-methacryloyloxyethyl phosphorylcholine)–poly(2-(diisopropylamino)ethyl methacrylate) (PMPC–PDPA) polymersomes as a suitable nanoscopic carrier to precisely and controllably deliver GCs within inflamed target cells. The in vitro cellular studies revealed that polymersomes ensure the stability, selectivity and bioavailability of the loaded drug within macrophages. At molecular level, we tested key inflammation-related markers, such as the nuclear factor-κB, tumour necrosis factor-α, interleukin-1β, and interleukin-6. With this, we demonstrated that pH responsive polymersomes are able to enhance the anti-inflammatory effect of loaded GC drug. Overall, we prove the potential of PMPC–PDPA polymersomes to efficiently promote the inflammation shutdown, while reducing the well-known therapeutic limitations in GC-based therapy.

Keywords: Inflammation, Macrophages, Glucocorticoid, Polymersomes

Campillo, N., Falcones, B., Otero, J., Colina, R., Gozal, D., Navajas, D., Farré, R., Almendros, I., (2019). Differential oxygenation in tumor microenvironment modulates macrophage and cancer cell crosstalk: Novel experimental settingand proof of concept Frontiers in Oncology 9, 43

Hypoxia is a common characteristic of many solid tumors that has been associated with tumor aggressiveness. Limited diffusion of oxygen generates a gradient of oxygen availability from the blood vessel to the interstitial space and may underlie the recruitment of macrophages fostering cancer progression. However, the available data based on the recruitment of circulating cells to the tumor microenvironment has been so far carried out by conventional co-culture systems which ignore the hypoxic gradient between the vessel to the tumor interstitium. Here, we have designed a novel easy-to-build cell culture device that enables evaluation of cellular cross-talk and cell migration while they are being simultaneously exposed to different oxygenation environments. As a proof-of-concept of the potential role of differential oxygenation among interacting cells we have evaluated the activation and recruitment of macrophages in response to hypoxic melanoma, breast, and kidney cancer cells. We found that hypoxic melanoma and breast cancer cells co-cultured with normoxic macrophages enhanced their directional migration. By contrast, hypoxic kidney cells were not able to increase their recruitment. We also identified well-described hypoxia-induced pathways which could contribute in the immune cell recruitment (VEGFA and PTGS2 genes). Moreover, melanoma and breast cancer increased their proliferation. However, oxygenation levels affected neither kidney cancer cell proliferation nor gene expression, which in turn resulted in no significant changes in macrophage migration and polarization. Therefore, the cell culture device presented here provides an excellent opportunity for researchers to reproduce the in vivo hypoxic gradients in solid tumors and to study their role in recruiting circulating cells to the tumor in specific types of cancer.

Keywords: Hypoxia gradient, Macrophage motility, Models of host-tumor interactions, Novel assay technology, Tumor progression

Hervera, A., De Virgiliis, F., Palmisano, I., Zhou, L., Tantardini, E., Kong, G., Hutson, T., Danzi, M. C., Perry, R. B. T., Santos, C. X. C., Kapustin, A. N., Fleck, R. A., Del Río, J. A., Carroll, T., Lemmon, V., Bixby, J. L., Shah, A. M., Fainzilber, M., Di Giovanni, S., (2018). Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons Nature Cell Biology 20, (3), 307-319

Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal endosomes, active NOX2 is retrogradely transported to the cell body through an importin-β1–dynein-dependent mechanism. Endosomal NOX2 oxidizes PTEN, which leads to its inactivation, thus stimulating PI3K–phosporylated (p-)Akt signalling and regenerative outgrowth. Challenging the view that ROS are exclusively involved in nerve degeneration, we propose a previously unrecognized role of ROS in mammalian axonal regeneration through a NOX2–PI3K–p-Akt signalling pathway.

Keywords: Adult neurogenesis, Endocytosis, Exocytosis, Monocytes and macrophages, Stress signalling

Matalonga, J., Glaria, E., Bresque, M., Escande, C., Carbó, J. M., Kiefer, K., Vicente, R., León, T. E., Beceiro, S., Pascual-García, M., Serret, J., Sanjurjo, L., Morón-Ros, S., Riera, A., Paytubi, S., Juarez, A., Sotillo, F., Lindbom, L., Caelles, C., Sarrias, M. R., Sancho, J., Castrillo, A., Chini, E. N., Valledor, A. F., (2017). The nuclear receptor LXR limits bacterial infection of host macrophages through a mechanism that impacts cellular NAD metabolism Cell Reports 18, (5), 1241-1255

Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.

Keywords: Bacterial infection, CD38, Cytoskeleton, LXR, Macrophage, NAD, Nuclear receptor