Candida albicans Infection Affords Protection against Reinfection via Functional Reprogramming of Monocytes
Department of Medicine, Radboud University Nijmegen Medical Centre, The Netherlands.Cell host & microbe (Impact Factor: 12.33). 08/2012; 12(2):223-32. DOI: 10.1016/j.chom.2012.06.006
Immunological memory in vertebrates is often exclusively attributed to T and B cell function. Recently it was proposed that the enhanced and sustained innate immune responses following initial infectious exposure may also afford protection against reinfection. Testing this concept of "trained immunity," we show that mice lacking functional T and B lymphocytes are protected against reinfection with Candida albicans in a monocyte-dependent manner. C. albicans and fungal cell wall β-glucans induced functional reprogramming of monocytes, leading to enhanced cytokine production in vivo and in vitro. The training required the β-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. Monocyte training by β-glucans was associated with stable changes in histone trimethylation at H3K4, which suggests the involvement of epigenetic mechanisms in this phenomenon. The functional reprogramming of monocytes, reminiscent of similar NK cell properties, supports the concept of "trained immunity" and may be employed for the design of improved vaccination strategies.
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- "To address whether monocytes may gain potential " memory " from previous challenges, experimental systems were designed to provide simultaneous or sequential challenges to monocytes with multiple distinct stimulants . For example, monocytes with a prior challenge of beta-glucan were " trained " to respond with a more robust inflammatory response to a subsequent LPS challenge (Netea et al., 2011; Quintin et al., 2012). We reported that retinoic acid may synergize with IL-4 in triggering the expression of M2-type cellular mediators such as arginase 1, while co-stimulation of monocytes with IL-4/retinoic acid with LPS annihilate the expression of arginase 1 (Surace and Li, 2013). "
ABSTRACT: Recent progress harkens back to the old theme of immune memory, except this time in the area of innate immunity, to which traditional paradigm only prescribes a rudimentary first-line defense function with no memory. However, both in vitro and in vivo studies reveal that innate leukocytes may adopt distinct activation states such as priming, tolerance, and exhaustion, depending upon the history of prior challenges. The dynamic programming and potential memory of innate leukocytes may have far-reaching consequences in health and disease. This review aims to provide some salient features of innate programing and memory, patho-physiological consequences, underlying mechanisms, and current pressing issues.
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- "Monocytes stimulated with microbial products were demonstrated to acquire a long-lasting proinflammatory phenotype through induction of persistent epigenetic changes . Remarkably, a large number of genes with an altered epigenetic state are involved in atherosclerosis , suggesting the involvement of trained immunity in atherosclerosis  . Indeed, also oxLDL (in contrast to LDL) can promote trained immunity in monocytes via inducing persistent H3K4me3 modifications in promoter regions important to foam cell formation and cytokine production. "
ABSTRACT: Nowadays, epigenetic mechanisms involving DNA methylation, histone modifications and microRNA regulation emerge as important players in cardiovascular disease (CVD). Epigenetics may provide the missing link between environment, genome and disease phenotype and be responsible for the strong interindividual variation in disease risk factors underlying CVD. Daily diet is known to have a major influence on both the development and the prevention of CVD. Interestingly, the dietary lifestyle of our (grand)parents and of us contributes to CVD risk by metabolic (re)programming of our epigenome in utero, after birth or during life. In contrast to genetic mutations, the plasticity of CVD related epigenetic changes makes them attractive candidates for nutritional prevention or pharmacological intervention. Although a growing number of epidemiologic studies have shown a link between the ingestion of nutritional polyphenols and cardiovascular health benefits, potential involvement of epigenetic mechanisms has been underexplored. In this review, we will give an overview of epigenetic alterations in atherosclerosis, with the focus on DNA and histone modifications by chromatin-modifying proteins. Finally, we illustrate that cocoa flavanols and other classes of dietary molecules may promote cardiovascular health by targeting multiple classes of chromatin writer-reader-eraser proteins related to histone acetylation-methylation and DNA methylation.
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- "Emerging in vitro studies reveal that innate monocytes may adopt distinct phenotypes by prior conditioning or " training " with varying dosages of innate stimulants (Deng et al., 2013; Netea et al., 2011; Quintin et al., 2012). For example, pre-conditioning with super-low dose LPS " primes " the expression of selected pro-inflammatory mediators such as TNF-α and IL-12, while suppressing the expression of iNOS (Hirohashi and Morrison, 1996). "
ABSTRACT: Sepsis mortality varies dramatically in individuals of variable immune conditions, with poorly defined mechanisms. This phenomenon complements the hypothesis that innate immunity may adopt rudimentary memory, as demonstrated in vitro with endotoxin priming and tolerance in cultured monocytes. However, previous in vivo studies only examined the protective effect of endotoxin tolerance in the context of sepsis. In sharp contrast, we report herein that pre-conditioning with super-low or low dose endotoxin lipopolysaccharide (LPS) cause strikingly opposite survival outcomes. Mice pre-conditioned with super-low dose LPS experienced severe tissue damage, inflammation, increased bacterial load in circulation, and elevated mortality when they were subjected to cecal-ligation and puncture (CLP). This is in contrast to the well-reported protective phenomenon with CLP mice pre-conditioned with low dose LPS. Mechanistically, we demonstrated that super-low and low dose LPS differentially modulate the formation of neutrophil extracellular trap (NET) in neutrophils. Instead of increased ERK activation and NET formation in neutrophils pre-conditioned with low dose LPS, we observed significantly reduced ERK activation and compromised NET generation in neutrophils pre-conditioned with super-low dose LPS. Collectively, our findings reveal a mechanism potentially responsible for the dynamic programming of innate immunity in vivo as it relates to sepsis risks.
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