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Resident macrophages are distributed across all tissues and are highly heterogeneous due to adaptation to different tissue-specific environments. The resident macrophages of the sensory ganglia (sensory neuron-associated macrophages, sNAMs) are in close contact with the cell body of primary sensory neurons and might play physiological and pathophysiological roles. After peripheral nerve injury, there is an increase in the population of macrophage in the sensory ganglia, which have been implicated in different conditions, including neuropathic pain development. However, it is still under debate whether macrophage accumulation in the sensory ganglia after peripheral nerve injury is due to the local proliferation of resident macrophages or a result of blood monocyte infiltration. Here, we confirmed that the number of macrophages increased in the sensory ganglia after the spared nerve injury (SNI) model in mice. Using different approaches, we found that the increase in the number of macrophages in the sensory ganglia after SNI is a consequence of the proliferation of resident CX3CR1+ macrophages, which participate in the development of neuropathic pain, but not due to infiltration of peripheral blood monocytes. These proliferating macrophages are the source of pro-inflammatory cytokines such as TNF and IL-1b. In addition, we found that CX3CR1 signaling is involved in the sNAMs proliferation and neuropathic pain development after peripheral nerve injury. In summary, these results indicated that peripheral nerve injury leads to sNAMs proliferation in the sensory ganglia in a CX3CR1-dependent manner accounting for neuropathic pain development. In conclusion, sNAMs proliferation could be modulated to change pathophysiological conditions such as chronic neuropathic pain.

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of “long COVID-19” syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell–derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction. SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (ATMale wild-type (WT) C57BL/6 mice either with the ATATOur findings show that AT

Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, the long-term neuropsychiatric dysfunction has been frequently observed after mild infection. Here we show the spectrum of the cerebral impact of SARS-CoV-2 infection ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal trans-ethmoidal approach) from individuals who died of COVID-19. We used surface-based analyses of 3T MRI and identified orbitofrontal cortical atrophy in a group of 81 mildly infected patients (77% referred anosmia or dysgeusia during acute stage) compared to 145 healthy volunteers; this atrophy correlated with symptoms of anxiety and cognitive dysfunction. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection, and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these 5 patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a non-canonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes and consequently leads to neuronal death or dysfunction. These deregulated processes are also likely to contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

A dor neuropática é uma condição debilitante causada por danos no sistema nervoso somatossensorial, como lesões dos nervos periféricos. As células do sistema imune, em particular os monócitos/macrófagos, desempenham um papel fundamental no desenvolvimento deste processo. Embora diversos estudos sugiram o envolvimento dessas células na medula espinal e gânglio da raiz dorsal (GRD) após a indução da neuropatia, a caracterização funcional e fenotípica, bem como a origem dessas células nesses órgãos, ainda não está esclarecida. Na medula espinal, estudos recentes têm demonstrado que apesar da massiva ativação e proliferação da micróglia residente, não há recrutamento de células mielóides para esse tecido após a indução da neuropatia, divergindo dos dados anteriormente descritos na literatura. Diante desses estudos controversos, iniciamos nosso trabalho demonstrando que possivelmente as células mielóides não são capazes de ultrapassar a barreira hematoencefálica e infiltrar na medula espinal após a indução da neuropatia periférica pelo modelo de SNI e assim, a ativação microglial ocorre de maneira independente do infiltrado dessas células neste tecido. No que se refere aos GRDs, trabalhos anteriores demonstram que há um aumento dos marcadores de ativação de macrófagos nesse tecido após a lesão periférica. Com isso, nós caracterizamos as subpopulações de monócitos/macrófagos presentes no GRD e identificamos, células CX3CR1+ e células CCR2+. De maneira interessante, ao isolarmos as células CX3CR1+ observamos que esse subtipo celular possa ser as principais células responsáveis pela produção dos mediadores inflamatórios no GRD após indução de SNI, enquanto as células CCR2+ parecem contribuir apenas de maneira parcial para a produção de IL-1? e TNF-? neste tecido, uma vez que a expressão desses mediadores não foi totalmente suprimida na ausência desse subtipo celular. Por fim, investigamos a origem desses subtipos de monócitos presentes no GRD. Por meio da parabiose entre animais wild type e GFP+, observamos que embora haja um pequeno aumento de células GFP+ no GRD de animais lesionados, essas células não são macrófagos. Corroborando com esses dados, ao realizarmos a parabiose de animais wild type com animais CX3CR1GFP/+CCR2RFP/+ não observamos presença de células CX3CR1 ou CCR2 no GRD após SNI. Em conjunto, nossos dados demonstram que existem duas subpopulações de monócitos no GRD, sendo uma delas residente e contribuindo de maneira efetiva para a produção dos mediadores inflamatórios locais e outra população de células CCR2+ que podem ter um papel mais relevante no sítio da lesão e assim, a exacerbação da inflamação local pode interferir indiretamente, na ativação das células presentes nos GRDs, bem como na produção dos mediadores inflamatórios no tecido, que vão contribuir para o desenvolvimento da dor neuropática. Neuropathic pain is a debilitating disease due to severe damage to the nervous system, induced by peripheral nerve injury. The cells of the immune system, especially monocytes/macrophages, played a critical role in these process. Several projects have been suggested the role of these cells in the spinal cord and dorsal root ganglia (DRG) after neuropathic pain induction, but the functional and phenotypic characterization, as well as the source of cells, is still unclear. In the spinal cord, recent studies have shown that although massive activation and proliferation of the microglial occurred, there is no recruitment of myeloid cells to this tissue after the neuropathic pain induction, but this is contrary to previous findings in the literature. Based on this controversial studies, we first showed that myeloid cells are not able to overcome the blood-brain barrier and infiltrate in the spinal cord after the peripheral nerve injury by SNI model and thus, the microglial activation occurs independent of the infiltration of these cells in this tissue. With regard to DRGs, previous work has shown that there is an increase in the activation markers of macrophages after peripheral nerve injury.Thus, we characterized the subpopulations of monocytes/macrophages in the DRG and we identified CX3CR1+ and CCR2+ cells. Interestingly, when isolating the CX3CR1+ cells, we observed that this cell subtype may be the main cells responsible for the production of inflammatory mediators in the DRG after SNI induction, whereas CCR2+ cells appear to contribute only partially to the production of IL-1? and TNF-? in this tissue, since the expression of these mediators was not completely suppressed in the absence of this cellular subtype. Finally, we investigated the origin of these monocyte subtypes present in the DRG. Through parabiosis between wild type and GFP+ animals, we observed that although there is a small increase of GFP+ cells in the DRG of injured animals, these cells are not macrophages. Corroborating with these data, when performing the wild type parabiosis with CX3CR1GFP /+ CCR2RFP/+ animals, we did not observe the presence of CX3CR1 or CCR2 cells in the GRD after SNI. Finally, our data demonstrate that there are two subpopulations of monocytes in the DRG, one of them residing and contributing effectively to the production of local inflammatory mediators and another population of CCR2 cells that may have a more relevant role at the lesion site and thus, the exacerbation of local inflammation may indirectly interfere, in the activation of the cells present in the DRGs, as well as in the production of inflammatory mediators in the tissue, which will contribute to the development of neuropathic pain.

Background Triatomines are blood-sucking vectors of Trypanosoma cruzi, the causative agent of Chagas disease. During feeding, triatomines surpass the skin host response through biomolecules present in their saliva. Dendritic cells (DCs) play a crucial role in the induction of the protection to aggressive agents, including blood-sucking arthropods. Here, we evaluated if salivary components of triatomines from different genera evade the host immunity by modulating the biology and the function of LPS- or T. cruzi-stimulated DCs. Methods Saliva of Panstrongylus lignarius, Meccus pallidipennis, Triatoma lecticularia and Rhodnius prolixus were obtained by dissection of salivary glands and the DCs were obtained from the differentiation of mouse bone marrow precursors. Results The differentiation of DCs was inhibited by saliva of all species tested. Saliva differentially inhibited the expression of MHC-II, CD40, CD80 and CD86 in LPS-matured DCs. Except for the saliva of R. prolixus, which induced IL-6 cytokine production, TNF-α, IL-12 and IL-6 were inhibited by the saliva of the other three tested species and IL-10 was increased in all of them. Saliva per se, also induced the production of IL-12, IL-6 and IL-10. Only the saliva of R. prolixus induced DCs apoptosis. The presence of PGE2 was not detected in the saliva of the four triatomines studied. Finally, T. cruzi invasion on DCs is enhanced by the presence of the triatomine saliva. Conclusions These results demonstrate that saliva from different triatomine species exhibit immunomodulatory effects on LPS and T. cruzi-stimulated DCs. These effects could be related to hematophagy and transmission of T. cruzi during feeding. Electronic supplementary material The online version of this article (doi:10.1186/s13071-016-1890-x) contains supplementary material, which is available to authorized users.