Ravid Shechter

Infiltrating Blood-Derived Macrophages Are Vital Cells Playing an Anti-inflammatory Role in Recovery from Spinal Cord Injury in Mice

Using a mouse model of spinal injury, Michal Schwartz and colleagues tested the effect of macrophages on the recovery process and demonstrate an important anti-inflammatory role for a subset of infiltrating monocyte-derived macrophages that is dependent upon their expression of interleukin 10.

Toll-like receptors modulate adult hippocampal neurogenesis

Neurogenesis — the formation of new neurons in the adult brain — is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes. The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila and innate immune activity in mammals, regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCα/β-dependent activation of the NF-κB signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal.

The bright side of the glial scar in CNS repair.

Following CNS injury, in an apparently counterintuitive response, scar tissue formation inhibits axonal growth, imposing a major barrier to regeneration. Accordingly, scar-modulating treatments have become a leading therapeutic goal in the field of spinal cord injury. However, increasing evidence suggests a beneficial role for this scar tissue as part of the endogenous local immune regulation and repair process. How can these opposing effects be reconciled? Perhaps it is all a matter of timing.

Systemic inflammatory cells fight off neurodegenerative disease

Treatment of Alzheimer disease or amyotrophic lateral sclerosis with anti-inflammatory drugs (to prevent disease or slow its progression) has yielded mixed results, despite evidence indicating that local cytotoxic inflammation occurs in these conditions. Here, through consideration of the importance of immune cell origin (resident versus blood-derived immune cells) and activity (pro-inflammatory versus anti-inflammatory activity) under neurodegenerative conditions, we propose a model that reconciles these seemingly inconsistent data. We suggest that systemic immune cells (CD4+ T cells and peripheral blood-derived monocytes) must be recruited to the CNS to modify potentially destructive local inflammation, and that the failure of systemic anti-inflammatory drug therapies to arrest neurodegenerative disease progression might result from drug-induced suppression of such recruitment. Thus, we propose that an appreciation of the distinctive temporal and spatial contributions of resident and systemic leukocytes to disease progression is essential for the development of effective therapeutic regimens.

Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation.

Background Chondroitin sulfate proteoglycan (CSPG) is a major component of the glial scar. It is considered to be a major obstacle for central nervous system (CNS) recovery after injury, especially in light of its well-known activity in limiting axonal growth. Therefore, its degradation has become a key therapeutic goal in the field of CNS regeneration. Yet, the abundant de novo synthesis of CSPG in response to CNS injury is puzzling. This apparent dichotomy led us to hypothesize that CSPG plays a beneficial role in the repair process, which might have been previously overlooked because of nonoptimal regulation of its levels. This hypothesis is tested in the present study. Methods and Findings We inflicted spinal cord injury in adult mice and examined the effects of CSPG on the recovery process. We used xyloside to inhibit CSPG formation at different time points after the injury and analyzed the phenotype acquired by the microglia/macrophages in the lesion site. To distinguish between the resident microglia and infiltrating monocytes, we used chimeric mice whose bone marrow-derived myeloid cells expressed GFP. We found that CSPG plays a key role during the acute recovery stage after spinal cord injury in mice. Inhibition of CSPG synthesis immediately after injury impaired functional motor recovery and increased tissue loss. Using the chimeric mice we found that the immediate inhibition of CSPG production caused a dramatic effect on the spatial organization of the infiltrating myeloid cells around the lesion site, decreased insulin-like growth factor 1 (IGF-1) production by microglia/macrophages, and increased tumor necrosis factor alpha (TNF-α) levels. In contrast, delayed inhibition, allowing CSPG synthesis during the first 2 d following injury, with subsequent inhibition, improved recovery. Using in vitro studies, we showed that CSPG directly activated microglia/macrophages via the CD44 receptor and modulated neurotrophic factor secretion by these cells. Conclusions Our results show that CSPG plays a pivotal role in the repair of injured spinal cord and in the recovery of motor function during the acute phase after the injury; CSPG spatially and temporally controls activity of infiltrating blood-borne monocytes and resident microglia. The distinction made in this study between the beneficial role of CSPG during the acute stage and its deleterious effect at later stages emphasizes the need to retain the endogenous potential of this molecule in repair by controlling its levels at different stages of post-injury repair.

Harnessing monocyte-derived macrophages to control central nervous system pathologies: no longer ‘if’ but ‘how’

The central nervous system (CNS) tissues, including the brain, the eye, and the spinal cord, are immune‐privileged, secluded from the circulation by a complex of barriers, and equipped with their own myeloid cell population, the resident microglia. Based on the classical perspective of immune–brain interactions and on the contribution of such interactions to the progression of multiple sclerosis, an autoimmune inflammatory disease of the CNS, infiltrating macrophages were traditionally viewed as an enemy of the nervous system. However, over the past two decades, research has revealed the pivotal role of monocyte‐derived macrophages in CNS repair, and opened up a new era in understanding and treating CNS pathologies. Here, we gather current knowledge regarding macrophage broad spectrum of activities in the CNS, whose two poles correspond to the classical pro‐inflammatory M1 and the ‘alternatively‐activated’ M2 cells previously described in various non‐CNS pathologies, and their diverse, multi‐functional contribution in various neurological conditions, ranging from acute traumas to neurodegenerative disorders, and autoimmune diseases. The diverse functions are manifested by induction and resolution of inflammation as well as their involvement in neural tissue regeneration and renewal, matrix remodelling, debris clearance, and angiogenesis. A special focus is devoted to current evidence suggesting that resident microglia and infiltrating monocyte‐derived macrophages are functionally non‐redundant cell types. Taken together, these recent advances reveal a dramatic therapeutic opportunity for controlled harnessing of macrophages for repair of the damaged CNS following acute insults, in neurodegenerative conditions, and in psychiatric disorders.

Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates

Complex barriers separate immune-privileged tissues from the circulation. Here, we propose that cell entry to immune-privileged sites through barriers composed of tight junction-interconnected endothelium is associated with destructive inflammation, whereas border structures comprised of fenestrated vasculature enveloped by tightly regulated epithelium serve as active and selective immune-skewing gates in the steady state. Based on emerging knowledge of the central nervous system and information from other immune-privileged sites, we propose that these sites are endowed either with absolute endothelial-based barriers and epithelial gates that enable selective and educative transfer of trafficking leukocytes or with selective epithelial gates only.

New GABAergic interneurons supported by myelin-specific t cells are formed in intact adult spinal cord

Neural stem/progenitor cells are known to exist in the intact spinal cord, but the presence of newly formed neurons during adulthood has not been documented there to date. Here, we report the appearance of newly formed neurons under normal physiological conditions. These neurons are immature, express a GABAergic phenotype, and are primarily located in the dorsal part of the spinal cord. This localization appeared to be mediated by stromal‐derived factor‐1/CXC‐chemokine receptor‐4 signaling in the dorsal region. The extent of spinal cord neurogenesis was found to be greatly influenced by immune system integrity and in particular by myelin‐specific T cells. These observations provide evidence for in vivo spinal cord neurogenesis under nonpathological conditions and introduce novel mechanisms regulating adult spinal cord plasticity.

The glial scar-monocyte interplay: a pivotal resolution phase in spinal cord repair.

The inflammatory response in the injured spinal cord, an immune privileged site, has been mainly associated with the poor prognosis. However, recent data demonstrated that, in fact, some leukocytes, namely monocytes, are pivotal for repair due to their alternative anti-inflammatory phenotype. Given the pro-inflammatory milieu within the traumatized spinal cord, known to skew monocytes towards a classical phenotype, a pertinent question is how parenchymal-invading monocytes acquire resolving properties essential for healing, under such unfavorable conditions. In light of the spatial association between resolving (interleukin (IL)-10 producing) monocytes and the glial scar matrix chondroitin sulfate proteoglycan (CSPG), in this study we examined the mutual relationship between these two components. By inhibiting the de novo production of CSPG following spinal cord injury, we demonstrated that this extracellular matrix, mainly known for its ability to inhibit axonal growth, serves as a critical template skewing the entering monocytes towards the resolving phenotype. In vitro cell culture studies demonstrated that this matrix alone is sufficient to induce such monocyte polarization. Reciprocal conditional ablation of the monocyte-derived macrophages concentrated at the lesion margins, using diphtheria toxin, revealed that these cells have scar matrix-resolving properties. Replenishment of monocytic cell populations to the ablated mice demonstrated that this extracellular remodeling ability of the infiltrating monocytes requires their expression of the matrix-degrading enzyme, matrix metalloproteinase 13 (MMP-13), a property that was found here to be crucial for functional recovery. Altogether, this study demonstrates that the glial scar-matrix, a known obstacle to regeneration, is a critical component skewing the encountering monocytes towards a resolving phenotype. In an apparent feedback loop, monocytes were found to regulate scar resolution. This cross-regulation between the glial scar and monocytes primes the resolution of this interim phase of spinal cord repair, thereby providing a fundamental platform for the dynamic healing response.

CNS sterile injury: just another wound healing?

The poor recovery of the central nervous system (CNS) after injury, coupled with its complex and immunologically-privileged nature, led to the belief that CNS repair is different from the repair of other tissues. Here, we consider CNS repair from a novel perspective, suggesting that CNS responses to injury resemble wound healing. Extrapolating the classical wound healing model suggests that poor CNS recovery is an outcome of insufficient resolution of interim reparative events that precede tissue regeneration and renewal, a state reminiscent of chronic/unresolved wounds. This comparison requires reevaluation of the inflammatory response, glial scarring, and barrier permeability, traditionally considered obstacles to CNS repair. Understanding the similarity to wound healing suggests new research directions and therapeutic avenues for CNS injuries.