Molecular immunology
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Molecular immunology · Oct 2017
MD-2 regulates LPS-induced NLRP3 inflammasome activation and IL-1beta secretion by a MyD88/NF-κB-dependent pathway in alveolar macrophages cell line.
Myeloid differentiation protein 2 (MD-2) is required in the recognition of lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and participates in LPS-induced alveolar macrophage (AM) inflammation during acute lung injury (ALI). Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome aggravates inflammation in LPS-induced ALI. However, there is currently little known about the relationship between MD-2 signaling and the NLRP3 inflammasome. ⋯ Conversely, over-expression of MD-2 not only heightened NLRP3, MyD88, and NF-κB p65 protein expression, it also aggravated the LPS-induced inflammatory response. Furthermore, the NF-κB inhibitor SN50 had a beneficial role in decreasing NLRP3 and caspase-1 mRNA and protein expression. The observations suggest that MD-2 helps to regulate LPS-induced NLRP3 inflammasome activation and the inflammatory response in NR8383 cells, and likely does so by affecting MyD88/NF-κB signaling.
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Molecular immunology · Sep 2017
ReviewDemyelination, strokes, and eculizumab: Lessons from the congenital CD59 gene mutations.
Neurological symptoms of patients with p. Cys89Tyr mutation in the CD59 gene include recurrent peripheral neuropathy resembling Guillain-Barré syndrome, characterized by sensory-motor demyelinating neuropathy with secondary axonal damage and moderate enhancement of the nerve roots on spine MRI, together with recurrent strokes and retinal involvement. Three additional mutations in CD59, leading to loss of function, have been described, and overall, 12/12 (100%) of patients with any mutation presented with neurological symptoms; 11/12 (92%) patients presented with recurrent peripheral neuropathy, 6/12 (50%) with recurrent strokes, and 1/12 (8%) with retinal involvement. ⋯ We then describe the relationship with demyelination. The lack of CD59 allows uncontrolled complement amplification following low-level spontaneous-, viral-, or post viral-induced complement activation, resulting in severe demyelination in the peripheral nervous system. It is interesting, and certainly encouraging, that after 3 years, following 4 patients with Cys89Tyr mutations who are treated with eculizumab, no strokes occurred and non-permanent neurological insults underwent resolution without any new neurological exacerbations.
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Molecular immunology · May 2017
Immune cells and mediators involved in the inflammatory responses induced by a P-I metalloprotease and a phospholipase A2 from Bothrops atrox venom.
Bothrops envenomations can promote severe inflammatory responses by inducing edema, pain, leukocyte recruitment and release of chemical mediators by local cells. In the present study, two toxins from Bothrops atrox venom (the P-I metalloprotease Batroxase and the acidic phospholipase A2 BatroxPLA2) were evaluated in relation to their inflammatory effects induced in vivo and in vitro, mainly focusing on the participation of different immune cells and inflammatory mediators. Both toxins mainly promoted acute inflammatory responses with significant recruitment of neutrophils in the early hours (1-4h) after administration into the peritoneal cavity of C57BL/6 mice, and increased infiltration of mononuclear cells especially after 24h. ⋯ Furthermore, both toxins were able to stimulate degranulation of RBL-2H3 mast cells, but with distinct concentration-dependent effects. Altogether, these results indicated that Batroxase and BatroxPLA2 promoted local and acute inflammatory responses related to macrophages and mast cells and to the production of several mediators. Our findings should contribute for better understanding the different mechanisms of toxicity induced by P-I metalloproteases and phospholipases A2 after snakebite envenomations.
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It is well known that cardiac dysfunction develops during sepsis in both humans and in rodents (rats, mice). These defects appear to be reversible, since after "recovery" from sepsis, cardiac dysfunction disappears and the heart returns to its function that was present before the onset of sepsis. Our studies, using in vivo and in vitro models, have demonstrated that C5a and its receptors (C5aR1 and C5aR2) play key roles in cardiac dysfunction developing during sepsis. ⋯ In addition, C5a interactions with C5aRs also caused reductions in CM homeostatic proteins that regulate cytosolic [Ca2+]i in CMs: sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) and Na+/Ca2+ exchanger (NCX). In the absence of C5a receptors, defects in SERCA2 and NCX in CMs after sepsis are strikingly attenuated. These observations suggest new strategies to protect the heart from dysfunction developing during sepsis.
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Molecular immunology · Sep 2016
MiR-146a modulates macrophage polarization in systemic juvenile idiopathic arthritis by targeting INHBA.
Monocytes from patients with systemic juvenile idiopathic arthritis (SJIA) have both features of classical activated M1 and alternatively activated M2 macrophages. An increasing number of studies have indicated that microRNAs (miRNAs) are critical regulators of monocyte polarization. Here, we focused on miR-146a expression in SJIA and investigated the function of miR-146a in monocyte polarization. ⋯ Additionally, INHBA overexpression rescued the reduced IL-6, IL-12, and TNF-α levels induced by miR-146a overexpression in M1 macrophages, and rescued the increased Arg1, CCL17, and CCL22 levels induced by miR-146a overexpression in M2 macrophages. Similarly, the effects of miR-146a inhibition in monocyte polarization were all partly reversed by INHBA inhibition. Taken together, the data suggest that miR-146a serves as a molecular regulator in monocyte polarization and might play an important role in monocytes from patients with SJIA.