Vasconcelos FM, Silva HLA, Poso SMV, Barroso MV, Lanzetti M, Rocha RS, Graça JS, Esmerino EA, Freitas MQ, Silva MC, Raices RSL, Granato D, Pimentel TC, Sant'Ana AS, Cruz AG, Valença SS. Probiotic Prato cheese attenuates cigarette smoke-induced injuries in mice. Food Res Int. 2019 Sep;123:697-703.
DOI: 10.1016/j.foodres.2019.06.001
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The efficacy of probiotic Prato cheese against the inflammatory and oxidative damage in mice organs induced by cigarette smoke exposure was investigated. Forty C57BL/6 male mice were assigned to four groups: (CS) exposed to cigarette smoke and fed regular chow; (CS + C) exposed to cigarette smoke and fed daily conventional cheese ad libitum; (CS + PC) exposed to cigarette smoke and fed daily probiotic (Lactobacillus casei-01) cheese ad libitum; and a control group (C) exposed to ambient smoke-free air and fed regular chow. Bronchoalveolar lavage (BAL), blood, gut and liver homogenates were used for biochemical assays. The (CS + PC) group exhibited fewer BAL leukocytes, reactive oxygen species (ROS), and BAL and gut lipid peroxidation than the (CS) and (CS + C) groups, which had findings similar to the (C) group. Probiotic cheese consumption did not change the red blood cell count, but lower lactate dehydrogenase (LDH) levels in plasma, inducible nitric oxide synthase (iNOS) and peroxynitrite expression were observed compared to the (CS) and (CS + C) groups, with findings similar to the (C) group. These results suggest that probiotic Prato cheese consumption reduced oxidative stress in the lungs, gut, and liver.
Barros JF, Waclawiak I, Pecli C, Borges PA, Georgii JL, Ramos-Junior ES, Canetti C, Courau T, Klatzmann D, Kunkel SL, Penido C, Canto FB, Benjamim CF. Role of Chemokine Receptor CCR4 and Regulatory T Cells in Wound Healing of Diabetic Mice. J Invest Dermatol. 2019 May;139(5):1161-1170.
DOI: 10.1016/j.jid.2018.10.039
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Wound healing is a well-coordinated process that involves inflammatory mediators and cellular responses; however, if any disturbances are present during this process, tissue repair is impaired. Chronic wounds are one of the serious long-term complications associated with diabetes mellitus. The chemokine receptor CCR4 and its respective ligands, CCL17 and CCL22, are involved in regulatory T cell recruitment and activation in inflamed skin; however, the role of regulatory T cells in wounds is still not clear. Our aim was to investigate the role of CCR4 and regulatory T cells in cutaneous wound healing in diabetic mice. Alloxan-induced diabetic wild- type mice (diabetic) developed wounds that were difficult to heal, differently from CCR4–/– diabetic mice (CCR4–/– diabetic), and also from anti-CCL17/22 or anti-CD25–injected diabetic mice that presented with accelerated wound healing and fewer regulatory T cells in the wound bed. Consequently, CCR4–/– diabetic mice also presented with alteration on T cells population in the wound and draining lymph nodes; on day 14, these mice also displayed an increase of collagen fiber deposition. Still, cytokine levels were decreased in the wounds of CCR4–/– diabetic mice on day 2. Our data suggest that the receptor CCR4 and regulatory T cells negatively affect wound healing in diabetic mice.
Abreu SC, Xisto DG, de Oliveira TB, Blanco NG, de Castro LL, Kitoko JZ, Olsen PC, Lopes-Pacheco M, Morales MM, Weiss DJ, Rocco PRM. Serum from Asthmatic Mice Potentiates the Therapeutic Effects of Mesenchymal Stromal Cells in Experimental Allergic Asthma. Stem Cells Transl Med. 2019 Mar;8(3):301-312.
DOI: 10.1002/sctm.18-0056
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Asthma is a chronic inflammatory disease characterized by airway inflammation and remodeling, which can lead to progressive decline of lung function. Although mesenchymal stromal cells (MSCs) have shown beneficial immunomodulatory properties in preclinical models of allergic asthma, effects on airway remodeling have been limited. Mounting evidence suggests that prior exposure of MSCs to specific inflammatory stimuli or environments can enhance their immunomodulatory properties. Therefore, we investigated whether stimulating MSCs with bronchoalveolar lavage fluid (BALF) or serum from asthmatic mice could potentiate their therapeutic properties in experimental asthma. In a house dust mite (HDM) extract asthma model in mice, unstimulated, asthmatic BALF-stimulated, or asthmatic serum-stimulated MSCs were administered intratracheally 24 hours after the final HDM challenge. Lung mechanics and histology; BALF protein, cellularity, and biomarker levels; and lymph-node and bone marrow cellularity were assessed. Compared with unstimulated or BALF-stimulated MSCs, serum-stimulated MSCs further reduced BALF levels of interleukin (IL)-4, IL-13, and eotaxin, total and differential cellularity in BALF, bone marrow and lymph nodes, and collagen fiber content, while increasing BALF IL-10 levels and improving lung function. Serum stimulation led to higher MSC apoptosis, expression of various mediators (transforming growth factor-β, interferon-γ, IL-10, tumor necrosis factor-α-stimulated gene 6 protein, indoleamine 2,3-dioxygenase-1, and IL-1 receptor antagonist), and polarization of macrophages to M2 phenotype. In conclusion, asthmatic serum may be a novel strategy to potentiate therapeutic effects of MSCs in experimental asthma, leading to further reductions in both inflammation and remodeling than can be achieved with unstimulated MSCs.
Magalhães KG, Luna-Gomes T, Mesquita-Santos F, Corrêa R, Assunção LS, Atella GC, Weller PF, Bandeira-Melo C, Bozza PT. Schistosomal Lipids Activate Human Eosinophils via Toll-Like Receptor 2 and PGD2 Receptors: 15-LO Role in Cytokine Secretion. Front Immunol. 2019 Jan 25;9:3161.
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Parasite-derived lipids may play important roles in host-pathogen interactions and immune evasion mechanisms. Remarkable accumulation of eosinophils is a characteristic feature of inflammation associated with parasitic disease, especially caused by helminthes. Infiltrating eosinophils are implicated in the pathogenesis of helminth infection by virtue of their capacity to release an array of tissue-damaging and immunoregulatory mediators. However, the mechanisms involved in the activation of human eosinophils by parasite-derived molecules are not clear. Here we investigated the effects and mechanisms of schistosomal lipids-induced activation of human eosinophils. Our results showed that stimulation of human eosinophils in vitro with total lipid extracts from adult worms of S. mansoni induced direct activation of human eosinophils, eliciting lipid droplet biogenesis, synthesis of leukotriene (LT) C4 and eoxin (EX) C4 (14,15 LTC4) and secretion of eosinophil pre-formed TGFβ. We demonstrated that main eosinophil activating components within S. mansoni lipid extract are schistosomal-derived lysophosphatidylcholine (LPC) and prostaglandin (PG)D2. Moreover, TLR2 is up-regulated in human eosinophils upon stimulation with schistosomal lipids and pre-treatment with anti-TLR2 inhibited both schistosomal lipids- and LPC-, but not PGD2-, induced lipid droplet biogenesis and EXC4 synthesis within eosinophils, indicating that TLR2 mediates LPC-driven human eosinophil activation. By employing PGD2 receptor antagonists, we demonstrated that DP1 receptors are also involved in various parameters of human eosinophil activation induced by schistosomal lipids, but not by schistosomal LPC. In addition, schistosomal lipids and their active components PGD2 and LPC, triggered 15-LO dependent production of EXC4 and secretion of TGFβ. Taken together, our results showed that schistosomal lipids contain at least two components—LPC and PGD2—that are capable of direct activation of human eosinophils acting on distinct eosinophil-expressed receptors, noticeably TLR2 as well as DP1, trigger human eosinophil activation characterized by production/secretion of pro-inflammatory and immunoregulatory mediators.
Gomes PS, Tanghe S, Gallego-Delgado J, Conde L, Freire-de-Lima L, Lima AC, Freire-de-Lima CG, Lima Junior JDC, Moreira O, Totino P, Rodriguez A, Todeschini AR, Morrot A. Targeting the Hexosamine Biosynthetic Pathway Prevents Plasmodium Developmental Cycle and Disease Pathology in Vertebrate Host. Front Microbiol. 2019 Feb 28;10:305.
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Cerebral malaria (CM) is a clinical syndrome involving irreversible and lethal signs of brain injury associated to infection by parasites of the genus Plasmodium. The pathogenesis of CM derives from infection-induced proinflammatory cytokines associated with cytoadherence of parasitized red blood cells to brain microvasculature. Glycoconjugates are very abundant in the surface of Plasmodium spp., and are critical mediators of parasite virulence in host–pathogen interactions. Herein, we show that 6-Diazo-5-oxo-L-norleucine (DON) therapeutically used for blocking hexosamine biosynthetic pathway leads to recovery in experimental murine cerebral malaria. DON-induced protection was associated with decreased parasitism, which severely reduced Plasmodium transmission to mosquitoes. These findings point to a potential use of DON in combination therapies against malaria.
