Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

Physiology of Microglia

During the past decade, mechanisms involved in the immune surveillance of the central nervous system (CNS) have moved to the forefront of neuropathological research mainly because of the recognition that most neurological disorders involve activation and, possibly, dysregulation of microglia, the intrinsic macrophages of the CNS. Increasing evidence indicates that, in addition to their well-established phagocytic function, microglia may also participate in the regulation of non specific inflammation as well as adaptive immune responses. This article focuses on the signals regulating microglia innate immune functions, the role of microglia in antigen presentation, and their possible involvement in the development of CNS immunopathology.

Immune function of microglia

Microglia are highly motile glial cells that are proposed to mediate synaptic pruning during neuronal circuit formation. Disruption of signaling between microglia and neurons leads to an excess of immature synaptic connections, thought to be the result of impaired phagocytosis of synapses by microglia. However, until now the direct phagocytosis of synapses by microglia has not been reported and fundamental questions remain about the precise synaptic structures and phagocytic mechanisms involved. Here we used light sheet fluorescence microscopy to follow microglia-synapse interactions in developing organotypic hippocampal cultures, complemented by a 3D ultrastructural characterization using correlative light and electron microscopy (CLEM). Our findings define a set of dynamic microglia-synapse interactions, including the selective partial phagocytosis, or trogocytosis (trogo-: nibble), of presynaptic structures and the induction of postsynaptic spine head filopodia by microglia. These findings allow us to propose a mechanism for the facilitatory role of microglia in synaptic circuit remodeling and maturation.

/pdf/microglia-remodel-synapses-by-presynaptic-trogocytosis-and-41u9kek78w.pdf

Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction

Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease.

Recent advances in defining the molecular signaling pathways that regulate the phagocytosis of apoptotic cells have improved our understanding of this complex and evolutionarily conserved process. Studies in mice and humans suggest that the prompt removal of dying cells is crucial for immune tolerance and tissue homeostasis. Failed or defective clearance has emerged as an important contributing factor to a range of disease processes. This review addresses how specific molecular alterations of engulfment pathways are linked to pathogenic states. A better understanding of the apoptotic cell clearance process in healthy and diseased states could offer new therapeutic strategies.

https://rupress.org/jcb/article-pdf/189/7/1059/1346912/jcb_201004096.pdf

Clearance of apoptotic cells: implications in health and disease

Microglia, the tissue macrophages of the brain, play a crucial role in recognition and phagocytic removal of apoptotic neurons. The microglial receptors for recognition of apoptotic neurons are not yet characterized. Here we established a co-culture model of primary microglia and cerebellar granule neurons to examine the receptor systems involved in recognition/uptake of apoptotic neurons. Treatment with 100 μM S-nitrosocysteine induced apoptosis of cerebellar neurons as indicated by nuclear condensation and phosphatidylserine exposure to the exoplasmic leaflet of the plasma membrane. Microglial cells were added to neurons 2 h after apoptosis induction and co-cultured for 6 h in the presence of ligands that inhibit recognition by binding to respective receptors. Binding/phagocytosis was determined after combined 4′,6-diamidino-2-phenylindole/propidium iodide (for apoptotic/necrotic neurons) and lectin staining (for microglia). Uptake of apoptotic neurons was reduced by N-acetylglucosamine or galactose, suggesting that recognition involves asialoglycoprotein-like lectins. Furthermore, the inhibition of microglial binding/uptake of apoptotic neurons by RGDS peptide suggests a role of microglial vitronectin receptor. As microglia selectively bind lipid vesicles enriched in phosphatidylserine and O-phospho-L-serine interfered with the uptake of apoptotic neurons, an involvement of phosphatidylserine receptor is rather likely. Apoptotic neurons do not release soluble signals that serve to attract or activate microglia. Collectively, these results suggest that apoptotic neurons generate a complex surface signal recognized by different receptor systems on microglia.

Phagocytic clearance of apoptotic neurons by Microglia/Brain macrophages in vitro: involvement of lectin-, integrin-, and phosphatidylserine-mediated recognition.

Introduction Arithmetic-Geometric preparation Group theoretic exceptionality Genus 0 condition Dickson polynomials and Redei functions Rational functions with Euclidean signature Sporadic cases of arithmetic exceptionality Bibliography.

The rational function analogue of a question of Schur and exceptionality of permutation representations

In 1923 Schur considered the following problem. Let f(X) be a polynomial with integer coefficients that induces a bijection on the residue fields Z/pZ for infinitely many primes p. His conjecture, that such polynomials are compositions of linear and Dickson polynomials, was proved by M. Fried in 1970. Here we investigate the analogous question for rational functions, also we allow the base field to be any number field. As a result, there are many more rational functions for which the analogous property holds. Some infinite series come from rational isogenies of elliptic curves and deformations. There are several sporadic examples which do not fit in any of the series we obtain. First we translate the arithmetic property to a question about finite permutation groups, and classify those groups which fulfill the necessary conditions. The proofs depend on the classification of the finite simple groups. Then we use arithmetic arguments to either rule out many cases, or to prove that the remaining cases indeed give rise to examples. This part is based on Mazur's classical results about rational points on the modular curves X_0(p) and X_1(p), results about Galois images in GL_2(p) coming from action of the absolute Galois group of Q on p-torsion points of elliptic curves, the theory of complex multiplication, and the techniques used in the inverse regular Galois problem.

Peter Müller

Papers

Phagocytic clearance of apoptotic neurons by Microglia/Brain macrophages in vitro: involvement of lectin-, integrin-, and phosphatidylserine-mediated recognition.

The rational function analogue of a question of Schur and exceptionality of permutation representations

The rational function analogue of a question of Schur and exceptionality of permutation representations

Exceptional Polynomials of Affine Type

A Weil-Bound Free Proof of Schur's Conjecture