A novel preparation for histological analyses of intraventricular macrophages in the embryonic brain.

Microglia colonize the brain starting on embryonic day (E) 9.5 in mice, and their population increases with development. We have previously demonstrated that some microglia are derived from intraventricular macrophages, which frequently infiltrate the pallium at E12.5. To address how the infiltration of intraventricular macrophages is spatiotemporally regulated, histological analyses detecting how these cells associate with the surrounding cells at the site of infiltration into the pallial surface are essential. Using two-photon microscopy-based in vivo imaging, we demonstrated that most intraventricular macrophages adhere to the ventricular surface. This is a useful tool for imaging intraventricular macrophages maintaining their original position, but this method cannot be used for observing deeper brain regions. Meanwhile, we found that conventional cryosection-based and naked pallial slice-based observation resulted in unexpected detachment from the ventricular surface of intraventricular macrophages and their mislocation, suggesting that previous histological analyses might have failed to determine their physiological number and location in the ventricular space. To address this, we sought to establish a methodological preparation that enables us to delineate the structure and cellular interactions when intraventricular macrophages infiltrate the pallium. Here, we report that brain slices pretreated with agarose-embedding maintained adequate density and proper positioning of intraventricular macrophages on the ventricular surface. This method also enabled us to perform the immunostaining. We believe that this is helpful for conducting histological analyses to elucidate the mechanisms underlying intraventricular macrophage infiltration into the pallium and their cellular properties, leading to further understanding of the process of microglial colonization into the developing brain.

Embryonic Pericytes Promote Microglial Homeostasis and Their Effects on Neural Progenitors in the Developing Cerebral Cortex.

Multifaceted microglial functions in the developing brain, such as promoting the differentiation of neural progenitors and contributing to the positioning and survival of neurons, have been progressively revealed. Although previous studies have noted the relationship between vascular endothelial cells and microglia in the developing brain, little attention has been given to the importance of pericytes, the mural cells surrounding endothelial cells. In this study, we attempted to dissect the role of pericytes in microglial distribution and function in developing mouse brains. Our immunohistochemical analysis showed that approximately half of the microglia attached to capillaries in the cerebral walls. Notably, a magnified observation of the position of microglia, vascular endothelial cells and pericytes demonstrated that microglia were preferentially associated with pericytes that covered 79.8% of the total capillary surface area. Through in vivo pericyte depletion induced by the intraventricular administration of a neutralizing antibody against platelet-derived growth factor receptor (PDGFR)ß (clone APB5), we found that microglial density was markedly decreased compared with that in control antibody-treated brains because of their low proliferative capacity. Moreover, in vitro coculture of isolated CD11b+ microglia and NG2+PDGFRα- cells, which are mostly composed of pericytes, from parenchymal cells indicated that pericytes promote microglial proliferation via the production of soluble factors. Furthermore, pericyte depletion by APB5 treatment resulted in a failure of microglia to promote the differentiation of neural stem cells into intermediate progenitors. Taken together, our findings suggest that pericytes facilitate microglial homeostasis in the developing brains, thereby indirectly supporting microglial effects on neural progenitors.SIGNIFICANCE STATEMENT This study highlights the novel effect of pericytes on microglia in the developing mouse brain. Through multiple analyses using an in vivo pericyte depletion mouse model and an in vitro coculture study of isolated pericytes and microglia from parenchymal cells, we demonstrated that pericytes contribute to microglial proliferation and support microglia in efficiently promoting the differentiation of neural stem cells into intermediate progenitors. Our present data provide evidence that pericytes function not only in the maintenance of cerebral microcirculation and blood brain barrier (BBB) integrity but also in microglial homeostasis in the developing cerebral walls. These findings will expand our knowledge and help elucidate the mechanism of brain development both in healthy and disease conditions.

Treatment strategy for BVO-ME based on long-term outcomes correlating retinal structure by OCT image and visual acuity.

BACKGROUND: Intravitreal anti-vascular endothelial growth factor (VEGF) is a mainstream treatment for reducing ME secondary to BRVO (BVO-ME). Regrettably, most reports of intravitreal anti-VEGF for BVO-ME have disclosed only short-term outcomes. Here, we characterized long-term indicators for the visual prognosis of patients with BVO-ME, including the correlation between retinal structure by OCT and visual acuity. METHODS: Patients with BVO-ME were retrospectively recruited based on clinical records in Kansai Medical University Hospital from June 2012 to March 2022. This study enrolled patients with vision loss who received intravitreal injection of anti-VEGF for BVO-ME. Inclusion criteria were that patients received intravitreal injection of anti-VEGF as their first treatment and were followed for at least 36 months. Exclusion criteria were those patients with ocular disease other than BRVO or who had been previously treated for BVO-ME. Patients were divided into two groups according to BCVA at the final visit: Group A (≥ 0.7) and Group B (< 0.7). RESULTS: Forty-seven eyes from 45 patients were assessed. The mean follow-up period from initial to final visit was 64.38 ± 15.07 (range, 38-100) months. BCVA in Group A (n = 32) was significantly greater than in Group B (n = 15) at all timepoints. The ratio that the number of eyes which the EZ band and the foveal bulge were intact in Group A was higher than in Group B (p = 0.0004 and p = 0.0002, respectively). The ratio that the number of eyes which recurrence SRD was observed by the final visit in Group A was lower than in Group B (p = 0.0485). CONCLUSIONS: The integrity of the EZ band and an intact foveal bulge were significant predictors for visual acuity. In contrast, recurrent SRD led to poor visual acuity in the long term, even if BCVA was good in the short term.

Two-photon microscopic observation of cell-production dynamics in the developing mammalian neocortex in utero.

Morphogenesis and organ development should be understood based on a thorough description of cellular dynamics. Recent studies have explored the dynamic behaviors of mammalian neural progenitor cells (NPCs) using slice cultures in which three-dimensional systems conserve in vivo-like environments to a considerable degree. However, live observation of NPCs existing truly in vivo, as has long been performed for zebrafish NPCs, has yet to be established in mammals. Here, we performed intravital two-photon microscopic observation of NPCs in the developing cerebral cortex of H2B-EGFP or Fucci transgenic mice in utero. Fetuses in the uterine sac were immobilized using several devices and were observed through a window made in the uterine wall and the amniotic membrane while monitoring blood circulation. Clear visibility was obtained to the level of 300 µm from the scalp surface of the fetus, which enabled us to quantitatively assess NPC behaviors, such as division and interkinetic nuclear migration, within a neuroepithelial structure called the ventricular zone at embryonic day (E) 13 and E14. In fetuses undergoing healthy monitoring in utero for 60 min, the frequency of mitoses observed at the apical surface was similar to those observed in slice cultures and in freshly fixed in vivo specimens. Although the rate and duration of successful in utero observations are still limited (33% for ≥10 min and 14% for 60 min), further improvements based on this study will facilitate future understanding of how organogenetic cellular behaviors occur or are pathologically influenced by the systemic maternal condition and/or maternal-fetal relationships.

Microglia extensively survey the developing cortex via the CXCL12/CXCR4 system to help neural progenitors to acquire differentiated properties.

Neocortical development proceeds through the formation of new zones in which neural-lineage cells are organized based on their differentiation status. Although microglia initially distribute homogeneously throughout the growing cerebral wall, they accumulate in the inner cytogenic zone, the ventricular zone (VZ) and the subventricular zone (SVZ) in the mid-embryonic stage. However, the roles of these cells remain to be elucidated. In this study, we found that microglia, despite being only a minor population of the cells that constitute the cerebral wall, promote the differentiation of neural progenitor cells by frequently moving throughout the cortex; their migration is mediated by the CXCL12/CXCR4 system. Pulse-chase experiments confirmed that microglia help Pax6+ stem-like cells to differentiate into Tbr2+ intermediate progenitors. Further, monitoring of microglia by live imaging showed that administration of AMD3100, an antagonist of CXCR4, dampened microglial movement and decreased microglial surveillance throughout the cortex. In particular, arrest of microglial motion led to a prominent decrease in the abundance of Tbr2+ cells in the SVZ. Based on our findings, we propose that extensive surveillance by microglia contributes to the efficient functioning of these cells, thereby regulating the differentiation of neural stem-like cells.

Glycerol monomycolate is a novel ligand for the human, but not mouse macrophage inducible C-type lectin, Mincle.

An array of lipidic compounds that constitute the cell wall of mycobacteria is recognized by host receptors. Examples include trehalose dimycolate (TDM), which is a major surface-exposed glycolipid of mycobacteria, that interacts with the macrophage inducible C-type lectin, Mincle, and exerts its highly potent adjuvant functions. Recent evidence has suggested that glycerol monomycolate (GroMM), another mycolate-containing lipid species produced by mycobacteria, can stimulate innate immune cells; however, its specific host receptors have yet to be identified. We here demonstrated that cell transfectants expressing human Mincle (hMincle) reacted to both TDM and GroMM, while those expressing mouse Mincle (mMincle) only reacted to TDM and failed to recognize GroMM. Studies using domain swap chimeras confirmed that the ectodomain of hMincle, but not that of mMincle, interacted with GroMM, and site-directed mutagenesis analyses revealed that short stretches of amino acid residues at positions 174-176 and 195-196 were involved in GroMM recognition. To further substantiate the differential recognition of GroMM by hMincle and mMincle, hMincle transgenic/mMincle knock-out mice (i.e. hMincle(+) mice) were established and compared with non-transgenic mice (i.e. mMincle(+) mice). We showed that macrophages derived from hMincle(+) mice were activated by GroMM and produced inflammatory cytokines, whereas those derived from mMincle(+) mice did not exhibit any reactivity to GroMM. Furthermore, local inflammatory responses were elicited in the GroMM-injected skin of hMincle(+), but not mMincle(+) mice. These results demonstrated that GroMM is a unique ligand for hMincle that is not recognized by mMincle.

Pathological findings of mammary gland carcinoma and hemangiosarcoma cases in two African wild dogs (Lycaon pictus).

There are few studies on diseases affecting endangered African wild dogs. We report our findings on malignant tumors in two African wild dogs. Case 1 was a 6-year-old intact female diagnosed with inflammatory mammary carcinoma with pulmonary metastasis. Case 2 was an 11-year-old male diagnosed with primary hemangiosarcoma of the left atrial coronary sulcus with metastasis to multiple organs. Additionally, the tumor had grown through the cardiac wall, causing cardiac tamponade. The identification of disease incidence trends provides important information which will allow for the early detection and treatment of malignant tumors, and aid in the conservation of this species.

Differences in collateral vessel formation after experimental retinal vein occlusion in spontaneously hypertensive rats and wild-type rats.

Objective: Retinal vein occlusion (RVO) can lead to visual impairment, but the development of collateral vessels can sometimes mitigate significant damage. This study aimed to investigate the relationship between collateral vessels and hypertension, the most common underlying condition associated with RVO, by comparing spontaneously hypertensive rats (SHRs) and wild-type Wister rats (WWRs). We also examined the differences between WWRs and SHRs in terms of sphingosine 1-phosphate receptor 1 (S1PR1) expression and its product nitric oxide synthase 3 (NOS3) expression, which are involved in the formation of collateral vessels after vascular occlusion. Methods: Laser photocoagulation (PC) was used to occlude one randomly selected retinal vein in WWRs and SHRs, and the area surrounding the occluded vessel was examined using optical coherence tomography angiography. If reperfusion of the occluded vessel occurred within 2 weeks, the vessel was re-occluded repeatedly by PC. The number of eyes with successfully occluded vessels accompanied by collateral vessels was recorded. Then, WWRs and SHRs were divided into the following four groups: 1) control (no treatment), 2) vehicle (20% DMSO), 3) S1PR1 agonist (2 mg/mL SEW2871), and 4) S1PR1 antagonist (0.25 mg/mL VPC 23019) groups. The drugs were administered intravitreally in all groups except the control. The number of laser shots required for successful RVO was recorded. Histological evaluation and quantitative real-time PCR of S1PR1 and NOS3 were performed to elucidate the mechanisms underlying collateral vessel formation. Results: The proportion of eyes achieving successful vein occlusion was lower in SHRs (4/12 eyes, 33.3%) than in WWRs (8/10 eyes, 80%, p = 0.043). NOS3 expression at 6 h after PC was significantly higher in WWRs than in SHRs (p = 0.021). In WWRs treated with SEW2871, vein occlusion failed in 7 of 10 eyes (70%). The expression of NOS3 was significantly higher in the SEW2871 treatment group than in the untreated group (p < 0.001). Furthermore, NOS3 expression was significantly higher after SEW2871 treatment in WWRs than in SHRs (p = 0.011). Conclusion: In hypertensive environments, collateral vessels are less likely to develop, and S1PR1 may be involved in this phenomenon.

Major T cell response to a mycolyl glycolipid is mediated by CD1c molecules in rhesus macaques.

Human CD1b molecules contain a maze of hydrophobic pockets and a tunnel capable of accommodating the unusually long, branched acyl chain of mycolic acids, an essential fatty acid component of the cell wall of mycobacteria. It has been accepted that CD1b-bound mycolic acids constitute a scaffold for mycolate-containing (glyco)lipids stimulating CD1b-restricted T cells. Remarkable homology in amino acid sequence is observed between human and monkey CD1b molecules, and indeed, monkey CD1b molecules are able to bind glucose monomycolate (GMM), a glucosylated species of mycolic acids, and present it to specific human T cells in vitro. Nevertheless, we found, unexpectedly, that Mycobacterium bovis bacillus Calmette-Guerin (BCG)-vaccinated monkeys exhibited GMM-specific T cell responses that were restricted by CD1c rather than CD1b molecules. GMM-specific, CD1c-restricted T cells were detected in the circulation of all 4 rhesus macaque monkeys tested after but not before vaccination with BCG. The circulating GMM-specific T cells were detected broadly in both CD4(+) and CD8(+) cell populations, and upon antigenic stimulation, a majority of the GMM-specific T cells produced both gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), two major host protective cytokines functioning against infection with mycobacteria. Furthermore, the GMM-specific T cells were able to extravasate and approach the site of infection where CD1c(+) cells accumulated. These observations indicate a previously inconceivable role for primate CD1c molecules in eliciting T cell responses to mycolate-containing antigens.

Th1-skewed tissue responses to a mycolyl glycolipid in mycobacteria-infected rhesus macaques.

Trehalose 6,6'-dimycolate (TDM) is a major glycolipid of the cell wall of mycobacteria with remarkable adjuvant functions. To avoid detection by the host innate immune system, invading mycobacteria down-regulate the expression of TDM by utilizing host-derived glucose as a competitive substrate for their mycolyltransferases; however, this enzymatic reaction results in the concomitant biosynthesis of glucose monomycolate (GMM) which is recognized by the acquired immune system. GMM-specific, CD1-restricted T cell responses have been detected in the peripheral blood of infected human subjects and monkeys as well as in secondary lymphoid organs of small animals, such as guinea pigs and human CD1-transgenic mice. Nevertheless, it remains to be determined how tissues respond at the site where GMM is produced. Here we found that rhesus macaques vaccinated with Mycobacterium bovis bacillus Calmette-Guerin mounted a chemokine response in GMM-challenged skin that was favorable for recruiting T helper (Th)1 T cells. Indeed, the expression of interferon-γ, but not Th2 or Th17 cytokines, was prominent in the GMM-injected tissue. The GMM-elicited tissue response was also associated with the expression of monocyte/macrophage-attracting CC chemokines, such as CCL2, CCL4 and CCL8. Furthermore, the skin response to GMM involved the up-regulated expression of granulysin and perforin. Given that GMM is produced primarily by pathogenic mycobacteria proliferating within the host, the Th1-skewed tissue response to GMM may function efficiently at the site of infection.

The microglia-blood vessel interactions in the developing brain.

Microglia are the immune cells in the central nervous system (CNS). Once microglial progenitors are generated in the yolk sac, these cells enter the CNS and colonize its structures by migrating and proliferating during development. Although the microglial population in the CNS is still low in this stage compared to adults, these cells can associate with many surrounding cells, such as neural lineage cells and vascular-structure-composing cells, by extending their filopodia and with their broad migration capacity. Previous studies revealed multifaceted microglial actions on neural lineage cells, such as regulating the differentiation of neural progenitors and modulating neuronal positioning. Notably, microglia not only act on neural lineage cells but also interact with blood vessels, for example, by supporting vascular formation and integrity. On the other hand, blood vessels contribute to microglial colonization into the CNS and their migration at local tissues. Importantly, pericytes, the cells that encompass vascular endothelial cells, have been suggested to play a profound role in microglial function. This review summarizes recent advances in the understanding of the interaction of microglia and blood vessels, especially focusing on the significance of this interaction in CNS development, and discusses how microglial and blood vessel dysfunction leads to developmental disorders.

The multifaceted roles of embryonic microglia in the developing brain.

Microglia are the resident immune cells of the central nervous system (CNS). Microglia originate from erythromyeloid progenitors in the yolk sac at the early embryonic stage, and these progenitors then colonize the CNS through extensive migration and proliferation during development. Microglia account for 10% of all cells in the adult brain, whereas the proportion of these cells in the embryonic brain is only 0.5-1.0%. Nevertheless, microglia in the developing brain widely move their cell body within the structure by extending filopodia; thus, they can interact with surrounding cells, such as neural lineage cells and vascular-structure-composing cells. This active microglial motility suggests that embryonic microglia play a pivotal role in brain development. Indeed, recent increasing evidence has revealed diverse microglial functions at the embryonic stage. For example, microglia control differentiation of neural stem cells, regulate the population size of neural progenitors and modulate the positioning and function of neurons. Moreover, microglia exert functions not only on neural lineage cells but also on blood vessels, such as supporting vascular formation and integrity. This review summarizes recent advances in the understanding of microglial cellular dynamics and multifaceted functions in the developing brain, with particular focus on the embryonic stage, and discusses the fundamental molecular mechanisms underlying their behavior.

CD206+ macrophages transventricularly infiltrate the early embryonic cerebral wall to differentiate into microglia.

The relationships between tissue-resident microglia and early macrophages, especially their lineage segregation outside the yolk sac, have been recently explored, providing a model in which a conversion from macrophages seeds microglia during brain development. However, spatiotemporal evidence to support such microglial seeding in situ and to explain how it occurs has not been obtained. By cell tracking via slice culture, intravital imaging, and Flash tag-mediated or genetic labeling, we find that intraventricular CD206+ macrophages, which are abundantly observed along the inner surface of the mouse cerebral wall, frequently enter the pallium at embryonic day 12. Immunofluorescence of the tracked cells show that postinfiltrative macrophages in the pallium acquire microglial properties while losing the CD206+ macrophage phenotype. We also find that intraventricular macrophages are supplied transepithelially from the roof plate. This study demonstrates that the "roof plate→ventricle→pallium" route is an essential path for microglial colonization into the embryonic mouse brain.

A microbial glycolipid functions as a new class of target antigen for delayed-type hypersensitivity.

Delayed-type hypersensitivity (DTH) is marked by high levels of protein antigen-specific T cell responses in sensitized individuals. Recent evidence has revealed a distinct pathway for T cell immunity directed against glycolipid antigens, but DTH to this class of antigen has been undetermined and difficult to prove due to their insolubility in aqueous solutions. Here, glucose monomycolate (GMM), a highly hydrophobic glycolipid of the cell wall of mycobacteria, was dispersed in aqueous solutions in the form of octaarginine-modified liposomes and tested for its ability to elicit cutaneous DTH responses in bacillus Calmette-Guerin (BCG)-immunized guinea pigs. After an intradermal challenge with the GMM liposome, a significant skin induration was observed in BCG-immunized, but not mock-treated, animals. The skin reaction peaked at around 2 days with local infiltration by mononuclear cells, and therefore, the response shared basic features with the classical DTH to protein antigens. Lymph node T cells from BCG-immunized guinea pigs specifically increased IFN-γ transcription in response to the GMM liposome, and this response was completely blocked by antibodies to CD1 lipid antigen-presenting molecules. Finally, whereas the T cells increased transcription of both T helper (Th) 1-type (IFN-γ and TNF-α) and Th2-type (IL-5 and IL-10) cytokines in response to the purified protein derivative or tuberculin, their GMM-specific response was skewed to Th1-type cytokine production known to be critical for protection against tuberculosis. Thus, our study reveals a novel form of DTH with medical implications.

Laminar and areal expression of unc5d and its role in cortical cell survival.

The UNC-5 family of netrin receptors is known to regulate axon guidance, cell migration, and cell survival. We have previously demonstrated that unc5d, one of the UNC-5 family member genes, is specifically expressed in layer 4 of the developing rat neocortex (Zhong Y, Takemoto M, Fukuda T, Hattori Y, Murakami F, Nakajima D, Nakayama M, Yamamoto N. 2004. Identification of the genes that are expressed in the upper layers of the neocortex. Cereb Cortex. 14:1144-1152). However, the role of UNC5D in cortical development is still unknown. In this study, we revealed that unc5d was highly expressed in the primary sensory areas of the mouse neocortex at around postnatal day 7. Netrin-4 was also found to be predominantly expressed in layer 4 of the sensory cortex and sensory thalamic nuclei. Cell surface binding assay showed that netrin-4 protein bound to UNC5D-expressing cells. An in vitro study further demonstrated that cell death of unc5d-expressing layer 4 cells was reduced by exogenous application of netrin-4 protein, whereas UNC5D is not sufficient to mediate the effect of netrin-4 in deep layer cells. Taken together, these results suggest that UNC5D is primarily expressed by layer 4 cells in the primary sensory areas of the developing neocortex and may mediate the effect of netrin-4 on cortical cell survival in a lamina-specific manner.

The behavior and functions of embryonic microglia.

Microglia are the resident immune cells of the central nervous system. Microglial progenitors are generated in the yolk sac during the early embryonic stage. Once microglia enter the brain primordium, these cells colonize the structure through migration and proliferation during brain development. Microglia account for a minor population among the total cells that constitute the developing cortex, but they can associate with many surrounding neural lineage cells by extending their filopodia and through their broad migration capacity. Of note, microglia change their distribution in a stage-dependent manner in the developing brain: microglia are homogenously distributed in the pallium in the early and late embryonic stages, whereas these cells are transiently absent from the cortical plate (CP) from embryonic day (E) 15 to E16 and colonize the ventricular zone (VZ), subventricular zone (SVZ), and intermediate zone (IZ). Previous studies have reported that microglia positioned in the VZ/SVZ/IZ play multiple roles in neural lineage cells, such as regulating neurogenesis, cell survival and neuronal circuit formation. In addition to microglial functions in the zones in which microglia are replenished, these cells indirectly contribute to the proper maturation of post-migratory neurons by exiting the CP during the mid-embryonic stage. Overall, microglial time-dependent distributional changes are necessary to provide particular functions that are required in specific regions. This review summarizes recent advances in the understanding of microglial colonization and multifaceted functions in the developing brain, especially focusing on the embryonic stage, and discuss the molecular mechanisms underlying microglial behaviors.

The Multiple Roles of Pericytes in Vascular Formation and Microglial Functions in the Brain.

In the capillary walls, vascular endothelial cells are covered with mural cells, such as smooth muscle cells and pericytes. Although pericytes had been thought to play simply a structural role, emerging evidence has highlighted their multiple functions in the embryonic, postnatal, and adult brain. As the central nervous system (CNS) develops, the brain's vascular structure gradually matures into a hierarchical network, which is crucial for the proper development of neural lineage cells by providing oxygen and nutrients. Pericytes play an essential role in vascular formation and regulate blood‒brain barrier (BBB) integrity as a component of the neurovascular unit (NVU), in collaboration with other cells, such as vascular endothelial cells, astrocytes, neurons, and microglia. Microglia, the resident immune cells of the CNS, colonize the brain at embryonic day (E) 9.5 in mice. These cells not only support the development and maturation of neural lineage cells but also help in vascular formation through their extensive migration. Recent studies have demonstrated that pericytes directly contact microglia in the CNS, and their interactions have a profound effect on physiological and pathological aspects. This review summarizes the function of pericytes, focusing on the interplay between pericytes and microglia.

Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology.

While amyloid-ß lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

Glycerol monomycolate, a latent tuberculosis-associated mycobacterial lipid, induces eosinophilic hypersensitivity responses in guinea pigs.

Dynamic changes in the lipid composition of the cell wall occur in pathogenic mycobacteria that are often intended for adaptation to the host environment. Dormant mycobacteria should have evolved efficient maneuvers for cohabitation, allowing the microbes to persist for years within the host. Glycerol monomycolate (GroMM) has been implicated as a specific immune target in human individuals with latent, but not active, tuberculosis, but the in vivo response to GroMM and the relevance of it to latent infection remain poorly understood. Here, we immunized guinea pigs with bacillus Calmette-Guerin (BCG) expressing high levels of GroMM and then, monitored skin reactions at the site of challenge with GroMM-containing liposome. We found that BCG-immunized guinea pigs mounted enhanced skin reactions to GroMM with prominent local infiltration by eosinophils. Consistent with this, GroMM-stimulated lymph node cells upregulated the expression of T helper (Th)2-type cytokines, such as interleukin (IL)-5 and IL-10, that could potentially counteract the microbe-eliminating Th1-type cytokine response. On the basis of these observations, we predict that the host response to GroMM produced by dormant mycobacteria would contribute to their long-term survival in the host.

[Molecular and cellular biology of mycobacteria].

The cell wall of mycobacteria contains mycobacteria-specific long-chain fatty acids, called mycolic acids, and mycolic acid-containing glycolipids. This highly hydrophobic structure of the cell wall of mycobacteria is critical not only for their acid-fast properties but also for their resistance to a variety of chemical attacks from the host cells, supporting their ability to survive for years within the host. On the other hand, the host T cells are capable of recognizing these critical lipid components of the cell wall of mycobacteria, such as glucose monomycolates, that are captured by group 1 CD1 molecules. These T cells are able to eliminate mycobacteria-infected cells. This opens the possibility for a new type of lipid-based vaccines against tuberculosis.