Jennings-Almeida B, Castelpoggi JP, Ramos-Junior ES, Ferreira EO, Domingues RMCP, Echevarria-Lima J, Coutinho-Silva R, Moreira-Souza ACA, Mariño E, Mackay CR, Zamboni DS, Bellio M, Scharfstein J, Lobo LA, Oliveira AC. Dietary Fiber Drives IL-1β-Dependent Peritonitis Induced by Bacteroides fragilis via Activation of the NLRP3 Inflammasome. J Immunol. 2021 May 15;206(10):2441-2452.

DOI: 10.4049/jimmunol.2000078

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Intestinal barrier is essential for dietary products and microbiota compartmentalization and therefore gut homeostasis. When this barrier is broken, cecal content overflows into the peritoneal cavity, leading to local and systemic robust inflammatory response, characterizing peritonitis and sepsis. It has been shown that IL-1β contributes with inflammatory storm during peritonitis and sepsis and its inhibition has beneficial effects to the host. Therefore, we investigated the mechanisms underlying IL-1β secretion using a widely adopted murine model of experimental peritonitis. The combined injection of sterile cecal content (SCC) and the gut commensal bacteria Bacteroides fragilis leads to IL-1β–dependent peritonitis, which was mitigated in mice deficient in NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome components. Typically acting as a damage signal, SCC, but not B. fragilis, activates canonical pathway of NLRP3 promoting IL-1β secretion in vitro and in vivo. Strikingly, absence of fiber in the SCC drastically reduces IL-1β production, whereas high-fiber SCC conversely increases this response in an NLRP3-dependent manner. In addition, NLRP3 was also required for IL-1β production induced by purified dietary fiber in primed macrophages. Extending to the in vivo context, IL-1β–dependent peritonitis was worsened in mice injected with B. fragilis and high-fiber SCC, whereas zero-fiber SCC ameliorates the pathology. Corroborating with the proinflammatory role of dietary fiber, IL-1R–deficient mice were protected from peritonitis induced by B. fragilis and particulate bran. Overall, our study highlights a function, previously unknown, for dietary fibers in fueling peritonitis through NLRP3 activation and IL-1β secretion outside the gut.

da Fonseca-Martins AM, de Souza Lima-Gomes P, Antunes MM, de Moura RG, Covre LP, Calôba C, Rocha VG, Pereira RM, Menezes GB, Gomes DCO, Saraiva EM, de Matos Guedes HL. Leishmania Parasites Drive PD-L1 Expression in Mice and Human Neutrophils With Suppressor Capacity. Front Immunol. 2021 Jun 15;12:598943.

DOI: 10.3389/fimmu.2021.598943

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Neutrophils play an important role in the outcome of leishmaniasis, contributing either to exacerbating or controlling the progression of infection, a dual effect whose underlying mechanisms are not clear. We recently reported that CD4+ and CD8+ T cells, and dendritic cells of Leishmania amazonensis-infected mice present high expression of PD-1 and PD-L1, respectively. Given that the PD-1/PD-L1 interaction may promote cellular dysfunction, and that neutrophils could interact with T cells during infection, we investigated here the levels of PD-L1 in neutrophils exposed to Leishmania parasites. We found that both, promastigotes and amastigotes of L. amazonensis induced the expression of PD-L1 in the human and murine neutrophils that internalized these parasites in vitro. PD-L1-expressing neutrophils were also observed in the ear lesions and the draining lymph nodes of L. amazonensis-infected mice, assessed through cell cytometry and intravital microscopy. Moreover, expression of PD-L1 progressively increased in neutrophils from ear lesions as the disease evolved to the chronic phase. Co-culture of infected neutrophils with in vitro activated CD8+ T cells inhibits IFN-γ production by a mechanism dependent on PD-1 and PD-L1. Importantly, we demonstrated that in vitro infection of human neutrophils by L braziliensis induced PD-L1+ expression and also PD-L1+ neutrophils were detected in the lesions of patients with cutaneous leishmaniasis. Taken together, these findings suggest that the Leishmania parasite increases the expression of PD-L1 in neutrophils with suppressor capacity, which could favor the parasite survival through impairing the immune response.

Keywords: Leishmania; PD-L1; human cutaneous leishmaniasis; murine leishmaniasis; neutrophils; skin; supression.

Vasconcellos LRC, Martimiano L, Dantas DP, Fonseca FM, Mata-Santos H, Travassos L, Mendez-Otero R, Bozza MT, Pimentel-Coelho PM. Intracerebral Injection of Heme Induces Lipid Peroxidation, Neuroinflammation, and Sensorimotor Deficits. Stroke. 2021 May;52(5):1788-1797.

DOI: 10.1161/STROKEAHA.120.031911

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Background and purpose: Heme is a red blood cell component released in the brain parenchyma following intracerebral hemorrhage. However, the study of the pathophysiological mechanisms triggered by heme in the brain is hampered by the lack of well-established in vivo models of intracerebral heme injection. This study aims to optimize and characterize a protocol of intrastriatal heme injection in mice, with a focus on the induction of lipid peroxidation, neuroinflammation and, ultimately, sensorimotor deficits. We also evaluated the involvement of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome sensor, in the behavior deficits induced by heme in this model.

Methods: Mice were injected with heme in the striatum for the evaluation of neuroinflammation and brain damage through histological and biochemical techniques. Immunoblot was used to evaluate the expression of proteins involved in heme/iron metabolism and antioxidant responses and the activation of the MAPK (mitogen-activated protein kinase) signaling pathway. For the assessment of neurological function, we followed-up heme-injected mice for 2 weeks using the rotarod, elevated body swing, and cylinder tests. Mice injected with the vehicle (sham), or autologous blood were used as controls.

Results: Heme induced lipid peroxidation and inflammation in the brain. Moreover, heme increased the expression of HO-1 (heme oxygenase-1), ferritin, p62, and superoxide dismutase 2, and activated the MAPK signaling pathway promoting pro-IL (interleukin)-1β production and its cleavage to the active form. Heme-injected mice exhibited signs of brain damage and reactive astrogliosis around the injection site. Behavior deficits were observed after heme or autologous blood injection in comparison to sham-operated controls. In addition, behavior deficits and IL-1β production were reduced in Nlrp3 knockout mice in comparison to wild-type mice.

Conclusions: Our results show that intracerebral heme injection induces neuroinflammation, and neurological deficits, in an NLRP3-dependent manner, suggesting that this is a feasible model to evaluate the role of heme in neurological.

Keywords: behavior; blood cells; cerebral hemorrhage; heme; inflammation.

Silva RCMC, Panis C, Pires BRB. Lessons from transmissible cancers for immunotherapy and transplant. Immunol Med. 2021 Dec 28:1-16.

DOI: 10.1080/25785826.2021.2018783

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The emergence of horizontal transmission of cancer between vertebrates is an issue that interests scientists and medical society. Transmission requires: (i) a mechanism by which cancer cells can transfer to another organism and (ii) a repressed immune response on the part of the recipient. Transmissible tumors are unique models to comprehend the responses and mechanisms mediated by the major histocompatibility complex (MHC), which can be transposed for transplant biology. Here, we discuss the mechanisms involved in immune-mediated tissue rejection, making a parallel with transmissible cancers. We also discuss cellular and molecular mechanisms involved in cancer immunotherapy and anti-rejection therapies.

Keywords: Transmissible cancer, MHC, transplant, immunotherapy