https://www.cell.com/trends/immunology/pdf/S1471-4906(07)00024-5.pdf

Astrocytes are active players in cerebral innate immunity

Post-traumatic cystic cavitation, in which the size and severity of a CNS injury progress from a small area of direct trauma to a greatly enlarged secondary injury surrounded by glial scar tissue, is a poorly understood complication of damage to the brain and spinal cord. Using minimally invasive techniques to avoid primary physical injury, this study demonstrates in vivo that inflammatory processes alone initiate a cascade of secondary tissue damage, progressive cavitation, and glial scarring in the CNS. An in vitro model allowed us to test the hypothesis that specific molecules that stimulate macrophage inflammatory activation are an important step in initiating secondary neuropathology. Time-lapse video analyses of inflammation-induced cavitation in our in vitro model revealed that this process occurs primarily via a previously undescribed cellular mechanism involving dramatic astrocyte morphological changes and rapid migration. The physical process of cavitation leads to astrocyte abandonment of neuronal processes, neurite stretching, and secondary injury. The macrophage mannose receptor and the complement receptor type 3 beta2-integrin are implicated in the cascade that induces cavity and scar formation. We also demonstrate that anti-inflammatory agents modulating transcription via the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma may be therapeutic in preventing progressive cavitation by limiting inflammation and subsequent secondary damage after CNS injury.

https://www.jneurosci.org/content/jneuro/19/19/8182.full.pdf

Cellular and Molecular Mechanisms of Glial Scarring and Progressive Cavitation: In Vivo and In Vitro Analysis of Inflammation-Induced Secondary Injury after CNS Trauma

Microglia mediate multiple facets of neuroinflammation, including cytotoxicity, repair, regeneration, and immunosuppression due to their ability to acquire diverse activation states, or phenotypes. Modulation of microglial phenotype is an appealing neurotherapeutic strategy but a comprehensive study of classical and more novel microglial phenotypic markers in vitro is lacking. The aim of this study was to outline the temporal expression of a battery of phenotype markers from polarised microglia to generate an in vitro tool for screening the immunomodulatory potential of novel compounds. We characterised expression of thirty-one macrophage/microglial phenotype markers in primary microglia over time (4, 12, 36, and 72 h), using RT-qPCR or multiplex protein assay. Firstly, we selected Interleukin-4 (IL-4) and lipopolysaccharide (LPS) as the strongest M1–M2 polarising stimuli, from six stimuli tested. At each time point, markers useful to identify that microglia were M1 included iNOS, Cox-2 and IL-6 and a loss of M2a markers. Markers useful for quantifying M2b-immunomodulatory microglia included, increased IL-1RA and SOCS3 and for M2a-repair and regeneration, included increased arginase-1, and a loss of the M1 and M2b markers were discriminatory. Additional markers were regulated at fewer time points, but are still likely important to monitor when assessing the immunomodulatory potential of novel therapies. Further, to facilitate identification of how novel immunomodulatory treatments alter the functional affects of microglia, we characterised how the soluble products from polarised microglia affected the type and rate of neuronal death; M1/2b induced increasing and M2a-induced decreasing neuronal loss. We also assessed any effects of prior activation state, to provide a way to identify how a novel compound may alter phenotype depending on the stage of injury/insult progression. We identified generally that a prior M1/2b reduced the ability of microglia to switch to M2a. Altogether, we have characterised a profile of phenotype markers and a mechanism of assessing functional outcome that we can use as a reference guide for first-line screening of novel immunomodulatory therapies in vitro in the search for viable neuroprotectants.

Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro.

Zebrafish Early Macrophages Colonize Cephalic Mesenchyme and Developing Brain, Retina, and Epidermis through a M-CSF Receptor-Dependent Invasive Process

Microglia are the resident brain macrophages and they have been traditionally studied as orchestrators of the brain inflammatory response during infections and disease In addition, microglia has a more benign, less explored role as the brain professional phagocytes Phagocytosis is a term coined from the Greek to describe the receptor-mediated engulfment and degradation of dead cells and microbes In addition, microglia phagocytoses brain-specific cargo, such as axonal and myelin debris in spinal cord injury or multiple sclerosis, amyloid-β deposits in Alzheimer's disease, and supernumerary synapses in postnatal development Common mechanisms of recognition, engulfment, and degradation of the different types of cargo are assumed, but very little is known about the shared and specific molecules involved in the phagocytosis of each target by microglia More importantly, the functional consequences of microglial phagocytosis remain largely unexplored Overall, phagocytosis is considered a beneficial phenomenon, since it eliminates dead cells and induces an anti-inflammatory response However, phagocytosis can also activate the respiratory burst, which produces toxic reactive oxygen species (ROS) Phagocytosis has been traditionally studied in pathological conditions, leading to the assumption that microglia have to be activated in order to become efficient phagocytes Recent data, however, has shown that unchallenged microglia phagocytose apoptotic cells during development and in adult neurogenic niches, suggesting an overlooked role in brain remodeling throughout the normal lifespan The present review will summarize the current state of the literature regarding the role of microglial phagocytosis in maintaining tissue homeostasis in health as in disease

/pdf/janus-faced-microglia-beneficial-and-detrimental-id6ywmrpl7.pdf

Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis

The immune competence of astrocytes is still ill defined, especially their endocytic capacity, a prerequisite for efficient antigen presentation. We show that mannose receptor, a very important conduit for internalization of infectious agents and self antigens, is functionally expressed in the murine CNS. By in vitro assays, astrocytes and microglia were shown to be the prime cells expressing this receptor. Studies on astrocytes demonstrate that its expression and function are inversely regulated by anti-and pro-inflammatory compounds. Downregulation of the mannose receptor by IFN-gamma is concomitant with the induction of the invariant chain, which is also induced by GM-CSF + IL-4. Mannose receptor-expressing astrocytes may thus act as scavenger not only in CNS development but also in defense, against soluble and particulate mannosylated pathogens, presenting fragments thereof at strategic locations in the CNS. These findings unravel a new and putatively very important role of astrocytes in innate immunity and possibly development.

Identification and functional characterization of the mannose receptor in astrocytes

The mannose receptor is a pattern-recognition receptor involved in innate and adaptive immunity. The receptor is mainly expressed by macrophages and, within the brain, by astrocytes and microglia. This study reports for the first time the effects of two classical proinflammatory (interferon-gamma, IFNgamma) and anti-inflammatory (interleukin-4, IL-4) cytokines on the levels of expression and activity of the mannose receptor expressed by mouse microglia, the brain resident macrophages. As observed for macrophages, IFNgamma treatment led to a decrease and IL-4 to an increase of mannose receptor expression. Consequently, the rates of pinocytosis were strongly upregulated by IL-4 and inhibited by IFNgamma. This latter, however, resumed with time and reached again the constitutive rate of pinocytosis. This recovery resulted from an increased pinocytic activity of the few mannose receptor molecules still expressed by IFNgamma-treated microglia. This may suggest a brain-specific regulation of the effects of IFNgamma since such a phenomenon has not been observed in macrophages. Together, these observations demonstrate that cytokine-stimulated immunocompetent microglia express a functional mannose receptor.

Functional characterization of mannose receptor expressed by immunocompetent mouse microglia.

The role of astrocytes and microglia as antigen-presenting cells in the brain is still controversial. In this study we have analyzed and compared aspects of the molecular machinery that underlies MHC class II trafficking in immunocompetent astrocytes and microglia. We show that IFN-gamma-stimulated microglia possess active cathepsin L and cathepsin S, and efficiently degrade the invariant chain, unlike IFN-gamma-stimulated astrocytes that express cathepsin L but not cathepsin S. The lack of cathepsin S proves to be dramatic for the antigen-presentation capacity of astrocytes, which is nearly abolished when these cells are stimulated by a combination of IFN-gamma and TNF-alpha. TNF-alpha indeed decreases cathepsin L activity as we show here, leading to alterations in invariant chain processing, and hence in MHC class II trafficking in astrocytes. Cystatin C inhibits cathepsin L activity in astrocytes, but does not regulate cathepsin L and cathepsin S activity in microglia. We therefore identify cathepsin L and cathepsin S as key components in the regulation of the immune potential of astrocytes and microglia, and provide evidence for a cell-specific regulation exerted by IFN-gamma and TNF-alpha on the expression and activity of cathepsins.

Immunocompetent astrocytes and microglia display major differences in the processing of the invariant chain and in the expression of active cathepsin L and cathepsin S

Astrocytes and microglia, two glial cell populations of the CNS, have been described to be involved in many immune processes. We used defined combinations of cytokines, interferon gamma (IFN-gamma)/interleukin-1 alpha (IL-1 alpha) and IFN-gamma/tumor necrosis factor alpha (TNF alpha), to simulate different in vitro immune environments observed in disease or inflammation. In these conditions, we analyzed and compared the regulating effects of these cytokines on cell surface and total expression of MHC II and on the capacity of murine astrocytes and microglia to present peptide and native antigens to specific primed T cells. Neither IL-1 alpha nor TNF alpha affected the IFN-gamma-induced antigen presentation capacity of microglia. Astrocytes, however, were severely impaired in their capacity to present native antigens and, to a minor extent, a peptide antigen. Total expression of MHC II was not affected by these cytokines in microglia, whereas in astrocytes it was reduced by IL-1 alpha and increased by TNF alpha. Both cytokines downregulated MHC II expression at the surface of astrocytes, but not of microglia. This shows that TNF alpha affects the of IFN-gamma-immunocompetent astrocytes to process and present antigen, probably either by altering membrane traffic of MHC II and of antigen and/or enzymatic activities associated with these mechanisms, while IL-1 alpha does so by downregulating MHC II expression. Altogether, our results illustrate how differently astrocytes and microglia react toward a defined, similar immune environment. One type of cell, the astrocytes, downregulate their T-cell stimulation and MHC II trafficking, and probably also their antigen processing, functions while the other, the microglia, maintain their antigen presentation potential.

Tumor necrosis factor alpha and interleukin-1 alpha inhibit through different pathways interferon-gamma-induced antigen presentation, processing and MHC class II surface expression on astrocytes, but not on microglia

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Identification and functional characterization of the mannose receptor in astrocytes

Functional characterization of mannose receptor expressed by immunocompetent mouse microglia.

Immunocompetent astrocytes and microglia display major differences in the processing of the invariant chain and in the expression of active cathepsin L and cathepsin S

Tumor necrosis factor alpha and interleukin-1 alpha inhibit through different pathways interferon-gamma-induced antigen presentation, processing and MHC class II surface expression on astrocytes, but not on microglia