CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.

Emerging evidence suggests that immune receptors may participate in many aging-related processes such as energy metabolism, inflammation, and cognitive decline. CD300f, a TREM2-like lipid-sensing immune receptor, is an exceptional receptor as it integrates activating and inhibitory cell-signaling pathways that modulate inflammation, efferocytosis, and microglial metabolic fitness. We hypothesize that CD300f can regulate systemic aging-related processes and ultimately healthy lifespan. We closely followed several cohorts of two strains of CD300f-/- and WT mice of both sexes for 30 months and observed an important reduction in lifespan and healthspan in knockout mice. This was associated with systemic inflammaging, increased cognitive decline, reduced brain glucose uptake observed by 18FDG PET scans, enrichment in microglial aging/neurodegeneration phenotypes, proteostasis alterations, senescence, increased frailty, and sex-dependent systemic metabolic changes. Moreover, the absence of CD300f altered macrophage immunometabolic phenotype. Taken together, we provide strong evidence suggesting that myeloid cell CD300f immune receptor contributes to healthy aging.

Nem mãezinha, nem mãezona. Mães, familiares e ativismo nos arredores da prisão / Not a mommy, not a mamma. Mothers, family and activism around the prison / Ni mamita, ni madraza. Madres, familiares y activismo en los alrededores de la prisión

Resumo O artigo aborda as ambiguidades dos lugares ocupados pelas mães e familiares a partir de limites e possibilidades de agenciamento no ativismo em torno das prisões. Discuto a atuação de mães em uma associação de familiares de presos chamada Amparar, com sede em São Paulo, seguindo os trajetos de Railda Alves, uma de suas fundadoras. A Amparar existe desde 2004 e desenvolve suas atividades em articulação com outras organizações que atuam no campo dos Direitos Humanos. O reconhecimento como mãe de preso e a enunciação tanto da potência do vínculo materno quanto do sofrimento dele decorrente fazem parte das negociações que envolvem o diálogo e o trabalho em rede com outras organizações, ativistas e instituições estatais. A figura da mãe permite a participação em determinadas atividades e a construção de trajetórias ativistas, mas opera também como limitadora em contextos que envolvem, sobretudo, as negociações com o Estado.

Abstract The article addresses the ambiguities of being mothers and family members con- sidering the limits and possibilities of agency in activism around prisons. I discuss the role of mothers in a Prisoners' Family Association named Amparar, located in São Paulo, following the paths of Railda Alves, one of its founders. Amparar exists since 2004 and develops its activities in conjunction with other organizations working in the field of Human Rights. The recognition as a prisoner's mother and the statement of both the strength of the maternal bond and the resulting suffering from it are part of the negotiations that involve dialogue and networking with other organizations, activists, and state institutions. The figure of the mother allows participation in certain activities and the construction of activist trajectories, but it also operates as a limiter in contexts that involve negotiations with the State.

Resumen El artículo aborda las ambigüedades de los lugares ocupados por madres y fami- liares desde los límites y posibilidades de agencia en el activismo en torno a las cárceles. Mi análisis si construye desde el papel de las madres en una asociación de familiares de presos llamada Amparar, con sede en São Paulo, siguiendo los caminos de Railda Alves, una de sus fundadoras. Amparar existe desde 2004 y desarrolla sus actividades en conjunto con otras organizaciones que trabajan en el campo de los Derechos Humanos. El reconocimiento como madre de un preso y la declaración tanto de la fuerza del vínculo materno como del sufrimien- to resultante son parte de las negociaciones que implican el diálogo y el networking con otras organizaciones, activistas e instituciones estatales. La figura de la madre permite la partici- pación en determinadas actividades y la construcción de trayectorias activistas, pero también opera como limitante en contextos que involucran, sobre todo, negociaciones con el Estado.

Mães e lutas por justiça. Encontros entre produção de conhecimento, ativismos e democracia / Mothers and struggles for justice. A meeting point between knowledge production, activism and democracy / Madres y luchas por la justicia. Encuentros entre producción de conocimiento, activismo y democracia

Resumo O artigo discute algumas das relações entre mães e processos de Estado, tendo em vista sobretudo os movimentos de mães e familiares de vítimas de violência institucional, as análises inaugurais a esse respeito nas ciências sociais brasileiras, as implicações dessas mães e familiares nas políticas de produção de conhecimento e na crise democrática que atravessamos. Na primeira parte do artigo, retomamos pesquisas fundamentais que constituíram o campo de estudos que pensa desde a perspectiva do envolvimento de mães em movimentos de reivindicação por direitos e justiça. A segunda parte do artigo propõe-se à apresentação de alguns dos desdobramentos, em nossas próprias pesquisas, desse envolvimento e da produção de um conhecimento compartilhado entre pesquisadoras e o que se denomina usualmente como "interlocutoras". A última parte do artigo discute a posicionalidade dos movimentos de mães e familiares de vítimas de violência junto ao que se tem chamado de "crise democrática brasileira". Com isso, buscamos oferecer uma contribuição para o campo de pesquisas que se voltam, já há algum tempo, à produção recíproca entre gênero e Estado.

Abstract The article discusses some of the relationships between mothers and State processes, especially in view of the movements of mothers and family members of victims of institutional violence, the inaugural analyzes in this regard in Brazilian social sciences, the implications of these mothers and family members in knowledge production, and the democratic crisis that we are going through. In the first section of the article, we return to fundamental research that has constituted the field of studies which think since the involvement of mothers in movements for rights and justice. The second section of the article presents someof the developments, in our own research, of this involvement and the shared knowledge production between researchers and what is usually called as "interlocutors". The last section of the article discusses the positionality of the movements of mothers and family members of victims of violence in what has been called the "Brazilian democratic crisis". Thereby, we seek to offer a contribution to the field of research that has been, for some time now, focused on the reciprocal production between gender and the State.

Resumen El artículo discute algunas de las relaciones entre las madres y los procesos del Estado, especialmente en vista de los movimientos de madres y familiares de víctimas de violencia institucional, los análisis inaugurales al respecto en las ciencias sociales brasileñas, las implicaciones de estas madres y familiares en las políticas de producción de conocimiento y la crisis democrática que atravesamos. En la primera parte del artículo, volvemos a las investigaciones fundamentales que constituyen el campo de estudios que piensa desde la implicación de las madres en movimientos de reivindicación de derechos y justicia. La segunda parte del artículo propone presentar algunos de los desarrollos, en nuestra propia investigación, de esta implicación y producción de conocimiento compartido entre investigadores y lo que habitualmente se denomina "interlocutores". La última parte del artículo analiza la posicionalidad de los movimientos de madres y familiares de víctimas de la violencia en lo que se ha denominado la "crisis democrática brasileña". Con ello, buscamos ofrecer un aporte al campo de las investigaciones que desde hace un tiempo están enfocadas en la producción recíproca entre género y Estado.

CD200 modulates spinal cord injury neuroinflammation and outcome through CD200R1.

The interaction between CD200 and its receptor CD200R1 is among the central regulators of microglia and macrophage phenotype. However, it remains to be established whether, in the context of a traumatic CNS injury, CD200R1 act as a negative regulator of these particular innate immune cells, and if the exogenous delivery of CD200 may ameliorate neurological deficits. In the present study, we first evaluated whether preventing the local interaction between the pair CD200-CD200R1, by using a selective blocking antibody against CD200R1, has a role on functional and inflammatory outcome after contusion-induced spinal cord injury (SCI) in mice. The injection of the αCD200R1, but not control IgG1, into the lesioned spinal cord immediately after the SCI worsened locomotor performance and exacerbated neuronal loss and demyelination. At the neuroimmunological level, we observed that microglial cells and macrophages showed increased levels of iNOS and Ly6C upon CD200R1 blockade, indicating that the disruption of CD200R1 drove these cells towards a more pro-inflammatory phenotype. Moreover, although CD200R1 blockade had no effect in the initial infiltration of neutrophils into the lesioned spinal cord, it significantly impaired their clearance, which is a key sign of excessive inflammation. Interestingly, intraparenchymal injection of recombinant CD200-His immediately after the injury induced neuroprotection and robust and long-lasting locomotor recovery. In conclusion, this study reveals that interaction of CD200-CD200R1 plays a crucial role in limiting inflammation and lesion progression after SCI, and that boosting the stimulation of this pathway may constitute a new therapeutic approach.

CD300f immunoreceptor contributes to peripheral nerve regeneration by the modulation of macrophage inflammatory phenotype.

BACKGROUND: It has recently become evident that activating/inhibitory cell surface immune receptors play a critical role in regulating immune and inflammatory processes in the central nervous system (CNS). The immunoreceptor CD300f expressed on monocytes, neutrophils, and mast cells modulates inflammation, phagocytosis, and outcome in models of autoimmune demyelination, allergy, and systemic lupus erythematosus. On the other hand, a finely regulated inflammatory response is essential to induce regeneration after injury to peripheral nerves since hematogenous macrophages, together with resident macrophages and de-differentiated Schwann cells, phagocyte distal axonal and myelin debris in a well-orchestrated inflammatory response. The possible roles and expression of CD300f and its ligands have not been reported under these conditions. METHODS: By using quantitative PCR (QPCR) and CD300f-IgG2a fusion protein, we show the expression of CD300f and its ligands in the normal and crush injured sciatic nerve. The putative role of CD300f in peripheral nerve regeneration was analyzed by blocking receptor-ligand interaction with the same CD300f-IgG2a soluble receptor fusion protein in sciatic nerves of Thy1-YFP-H mice injected at the time of injury. Macrophage M1/M2 polarization phenotype was also analyzed by CD206 and iNOS expression. RESULTS: We found an upregulation of CD300f mRNA and protein expression after injury. Moreover, the ligands are present in restricted membrane patches of Schwann cells, which remain stable after the lesion. The lesioned sciatic nerves of Thy1-YFP-H mice injected with a single dose of CD300f-IgG2a show long lasting effects on nerve regeneration characterized by a lower number of YFP-positive fibres growing into the tibial nerve after 10 days post lesion (dpl) and a delayed functional recovery when compared to PBS- or IgG2a-administered control groups. Animals treated with CD300f-IgG2a show at 10 dpl higher numbers of macrophages and CD206-positive cells and lower levels of iNOS expression than both control groups. At later time points (28 dpl), increased numbers of macrophages and iNOS expression occur. CONCLUSIONS: Taken together, these results show that the pair CD300f ligand is implicated in Wallerian degeneration and nerve regeneration by modulating both the influx and phenotype of macrophages.

Effects of Schwann cell transplants in an experimental nerve amputee model.

PURPOSE: By using a nerve amputee model of the rat sciatic nerve (Lago and Navarro, 2007), we have tested a strategy for the long-term maintenance of regenerated axons without distal target reinnervation, by grafting Schwann cells (SCs) into a capped silicone chamber containing the ending nerve stump. METHODS: The sciatic nerve of rats was transected and repaired with a silicone tube, the distal nerve was again cut at 10 mm and inserted in a capped tube that was filled with saline or with a suspension of cultured SCs. Transplants of SCs obtained from primary cultures have been compared with those of an immortalized SC line (SCTM41) or the same line overexpressing GDNF. RESULTS: The histological results show that nerve fibers were able to regenerate through a short distal nerve segment ending into the capped chamber, and sustain distal branches without degenerating for several months. There was abundant axonal sprouting forming an ending neuroma, and the caliber of myelinated fibers remained far thinner than normal during the 9 months investigated. With a distal transplant of primary SCs there were significantly more regenerated myelinated fibers than in the control group at 9 months, indicating that the grafted cells stimulated the axonal growth response and helped to maintain survival of axon branches. In contrast, axonal regeneration was significantly reduced with grafts of SCTM41 cells, probably due to physical competition between cell proliferation and axonal growth. SCTM41 cells overexpressing GDNF improved the regenerative response with respect to the parent SCTM41 cells, although not to the same extent as the primary SCs. CONCLUSION: A graft of primary SCs in the capped chamber stimulated axonal growth response and/or maintained survival of axonal branches on the long term in the nerve amputee model.

Evaluation of the long-term regenerative potential in an experimental nerve amputee model.

In this study, we evaluated the long-term maintenance of regenerated axons in an experimental nerve amputee model. The sciatic nerve of adult rats was transected and repaired with a silicone tube leaving a short gap; the distal nerve segment was again transected 10 mm distally and the distal stump either introduced in a capped silicone chamber (amputee group) or connected to denervated targets (tibial branch into the gastrocnemius muscle and peroneal nerve apposed to skin) (reinnervation group). Morphological studies were performed at 2.5, 6, and 9 months after surgery. In all cases, axons regenerated across the silicone tube and grew in the distal nerve segment. In the amputee group, the morphological results show the expected features of a neuroma that is formed when regenerating axons are prevented from reaching the end organs, with a large number of axonal profiles indicative of regenerative sprouting. The number of myelinated axons counted at the distal nerve was sustained over 9 months follow-up, indicating that regenerated axons are maintained chronically. Immunohistochemical labeling showed maintained expression of choline acetyltransferase, calcitonin gene-related peptide, and growth-related peptides 43 in the distal neuroma at 6 and 9 months. Reconnection of the distal nerve to foreign targets mildly improved the pattern of nerve regeneration, decreasing the number of excessive sprouts. These results indicate that axons regenerated may be eventually interfaced with external input-output systems over long time, even if ending in the absence of distal targets as will occur in amputee limbs.

Astrocyte-targeted expression of IL-6 protects the CNS against a focal brain injury.

The effect of CNS-targeted IL-6 gene expression has been thoroughly investigated in the otherwise nonperturbed brain but not following brain injury. Here we examined the impact of astrocyte-targeted IL-6 production in a traumatic brain injury (cryolesion) model using GFAP-IL6 transgenic mice. This study demonstrated that transgenic IL-6 production significantly increased wound healing following the cryolesion. Thus, at 20 days postlesion (dpl) the GFAP-IL6 mice showed almost complete wound healing compared to litter mate nontransgenic controls. It seems likely that a reduced inflammatory response in the long term could be responsible for this IL-6-related effect. Thus, while in the acute phase following cryolesion (1-6 dpl) the recruitment of macrophages and T lymphocytes was higher in GFAP-IL6 mice, at 10-20 dpl it was significantly reduced compared to controls. Reactive astrogliosis was also significantly increased up to but not including 20 dpl in the GFAP-IL6 mice. Oxidative stress as well as apoptotic cell death was significantly decreased throughout the time period studied in the GFAP-IL6 mice compared to controls. This could be linked to the altered inflammatory response as well as to the transgenic IL-6-induced increase of the antioxidant, neuroprotective proteins metallothionein-I + II. These results indicate that although in the brain the chronic astrocyte-targeted expression of IL-6 spontaneously induces an inflammatory response causing significant damage, during an acute neuropathological insult such as following traumatic injury, a clear neuroprotective role is evident.

Metallothionein-I overexpression decreases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin-6.

Transgenic expression of interleukin-6 (IL-6) in the CNS under the control of the glial fibrillary acidic protein (GFAP) gene promoter (GFAP-IL6 mice) causes significant damage and alters the expression of many genes, including a dramatic upregulation of metallothionein-I (MT-I). The findings in this report support the idea that the upregulation of MT-I observed in GFAP-IL6 mice is an important mechanism for coping with brain damage. Thus, GFAP-IL6 mice that were crossed with TgMTI transgenic mice (GFAP-IL6xTgMTI) and overexpressed MT-I in the brain showed a decreased upregulation of cytokines such as IL-6 and a diminished recruitment and activation of macrophages and T cells throughout the CNS but mainly in the cerebellum. The GFAP-IL6 mice showed clear evidence of increased oxidative stress, which was significantly decreased by MT-I overexpression. Interestingly, MT-I overexpression increased angiogenesis in GFAP-IL6 mice but not in control littermates. Overall, the results strongly suggest that MT-I+II proteins are valuable factors that protect against cytokine-induced CNS injury.

Metallothionein-1+2 deficiency increases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin 6.

Transgenic expression of IL-6 under the control of the GFAP gene promoter (GFAP-IL6 mice) in the CNS causes significant damage and alters the expression of many genes, including the metallothionein (MT) family, especially in the cerebellum. The crossing of GFAP-IL6 mice with MT-1+2 knock out (MTKO) mice provided evidence that the increased MT-1+2 expression normally observed in the GFAP-IL6 mice is an important mechanism for coping with brain damage. Thus, the GFAP-IL6xMTKO mice showed a decreased body weight gain and an impaired performance in the rota-rod test, as well as a higher upregulation of cytokines such as IL-6, IL-1alpha,beta, and TNFalpha and recruitment and activation of macrophages and T cells throughout the CNS but mainly in the cerebellum. Clear symptoms of increased oxidative stress and apoptotic cell death caused by MT-1+2 deficiency were observed in the GFAP-IL6xMTKO mice. Interestingly, MT-1+2 deficiency also altered the expected frequency of the offspring genotypes, suggesting a role of these proteins during development. Overall, the results suggest that the MT-1+2 proteins are valuable factors against cytokine-induced CNS injury.

Metallothionein-1+2 protect the CNS after a focal brain injury.

We have evaluated the physiological relevance of metallothionein-1+2 (MT-1+2) in the CNS following damage caused by a focal cryolesion onto the cortex. In comparison to normal mice, transgenic mice overexpressing the MT-1 isoform (TgMTI* mice) showed a significant decrease of the number of activated microglia/macrophage and of CD3+ T lymphocytes in the area surrounding the lesion, while astrocytosis was increased. The TgMTI* mice showed a diminished peripheral macrophage but not CD3 T cell response to the cryolesion. This altered inflammatory response produced a decreased expression of the proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha and an increased expression of the growth factors bFGF, TGFbeta1, and VEGF in the TgMTI* mice relative to control mice, which might be related to the increased angiogenesis and regeneration of the parenchyma of the former mice. The overexpression of MT-1 dramatically reduced the cryolesion-induced oxidative stress and neuronal apoptosis. Remarkably, these effects were also obtained by the intraperitoneal administration of MT-2 to both normal and MT-1+2 knock-out mice. These results fully support the notion that MT-1+2 are essential in the CNS for coping with focal brain injury and suggest a potential therapeutic use of these proteins.