HIV-1 gp120 influences the expression of microRNAs in human monocyte-derived dendritic cells via STAT3 activation

Background: MicroRNAs (miRs) are an abundant class of small non-coding RNAs (~22 nt) that reprogram gene ex- pression by targeting mRNA degradation and translational disruption. An emerging concept implicates miR coup- ling with transcription factors in myeloid cell development and function, thus contributing to host defense and inflammation. The important role that these molecules play in the pathogenesis of HIV-1 is only now emerging. Results: We provide evidence that exposure of monocyte-derived dendritic cells (MDDCs) to recombinant HIV-1 R5 gp120, but not to CCR5 natural ligand CCL4, influences the expression of a panel of miRs (i.e., miR-21, miR-155 and miR-181b) regulated by STAT3 and potentially targeting genes belonging to the STAT3 signaling pathway. The blockage of gp120-induced STAT3 activation impairs gp120 capacity to modulate the expression level of above mentioned miRs. Predictive analysis of miR putative targets emphasizes that these miRs share common target genes. Furthermore, gene ontology and pathway enrichment analysis outline that these genes mainly belong to biological processes related to regulation of transcription, in a complex network of interactions involving pathways relevant to HIV-DC interaction. Conclusions: Overall, these results point to gp120-triggered modulation of miR expression via STAT3 activation as a novel molecular mechanism exploited by HIV-1 to affect DC biology and thus modulate the immune response through complex regulatory loops involving, at the same time, miRs and transcription factors

Reciprocal Interactions between Lactoferrin and Bacterial Endotoxins and Their Role in the Regulation of the Immune Response

Lactoferrin (Lf), an iron-binding glycoprotein expressed in most biological fluids, represents a major component of the mammalian innate immune system. Lf’s multiple activities rely not only on its capacity to bind iron, but also to interact with molecular and cellular components of both host and pathogens. Lf can bind and sequester lipopolysaccharide (LPS), thus preventing pro-inflammatory pathway activation, sepsis and tissue damage. However, Lf-bound LPS may retain the capacity to induce cell activation via Toll-like receptor 4-dependent and -independent mechanisms. This review discusses the complex interplay between Lf and LPS and its relevance in the regulation of the immune response

Increased circulating levels of vitamin D binding protein in MS patients

Vitamin D (vitD) low status is currently considered a main environmental factor in multiple sclerosis (MS) etiology and pathogenesis. VitD and its metabolites are highly hydrophobic and circulate mostly bound to the vitamin D binding protein (DBP) and with lower affinity to albumin, while less than 1\% are in a free form. The aim of this study was to investigate whether the circulating levels of either of the two vitD plasma carriers and/or their relationship are altered in MS. We measured DBP and albumin plasma levels in 28 MS patients and 24 healthy controls. MS patients were found to have higher DBP levels than healthy subjects. Concomitant interferon beta therapy did not influence DBP concentration, and the difference with the control group was significant in both females and males. No significant correlation between DBP and albumin levels was observed either in healthy controls or in patients. These observations suggest the involvement of DBP in the patho-physiology of MS

Innate Lymphocytes in Adipose Tissue Homeostasis and Their Alterations in Obesity and Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer worldwide and a leading cause of death, with burden expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is associated with increased cancer incidence representing an important indicator of survival, prognosis, recurrence rates, and response to therapy for several tumors including CRC. Compelling evidence has been achieved that the low-grade chronic inflammation characterizing obesity represents a main factor that can favor carcinogenesis. Adipocytes and adipose tissue (AT) infiltrating immune cells contribute to obesity-related inflammation by releasing soluble factors affecting, both locally and systemically, the function of several cell types, including immune and cancer cells. The unbalanced production of immune mediators as well as the profound changes in the repertoire and activation state of immune cells in AT of obese subjects represent key events in the processes that set the basis for a pro-tumorigenic microenvironment. AT harbors a unique profile of immune cells of different origin that play an important role in tissue homeostasis. Among these, tissue-resident innate lymphocytes are emerging as important AT components whose depletion/aberrant activation occurring in obesity could have an impact on inflammation and immune-surveillance against tumors. However, a direct link between obesity-induced dysfunction and cancer development has not been demonstrated yet. In this review, we provide an overview of human obesity- and CRC-induced alterations of blood and adipose tissue-associated innate lymphocytes, and discuss how the adipose tissue microenvironment in obesity might influence the development of CRC

Editorial: diet, inflammation and colorectal cancer

This Research Topic was designed to provide the reader with an overview of the impact of body weight and adiposity, as well as of specific food compounds on the inflammatory status in health and disease states, such as CRC. We collected original and review articles featuring the role of specific food compounds in the regulation of immune response and their potential therapeutic implications, the effect of polyunsaturated fatty acids (PUFA), oligosaccharides, polyphenols and body weight in the modulation of inflammation and long-term disease outcomes, highlighting the link between diet, inflammation, and CRC

Distinct blood and visceral adipose tissue regulatory T cell and innate lymphocyte profiles characterize obesity and colorectal cancer

Visceral adipose tissue (VAT) is a main site where metabolic and immunologic processes interplay to regulate, at local and systemic level, the inflammatory status and immune response. Obesity-associated inflammation and immune dysfunctions are inextricably linked to tumor but, in spite of intense efforts, the mechanisms underpinning this asso- ciation remain elusive. In this report, we characterized the profile of VAT-associated and circulating innate lymphocyte and regulatory T (T reg ) cell subsets underlying inflammatory conditions, such as obesity and colorectal cancer (CRC). Analysis of NK, NKT-like, γδ T, and T reg cell populations in VAT and blood of healthy lean subjects revealed that CD56 hi NK and OX40 + T reg cells are more abundant in VAT with respect to blood. Conversely, CD56 dim NK and total T reg cells are most present in the circulation, while γδ T lymphocytes are uniformly distributed in the two compartments. Interestingly, a reduced frequency of circulating activated T reg cells, and a concomitant preferential enrichment of OX40- expressing T reg cells in VAT, were selectively observed in obese (Ob) subjects, and directly correlated with body mass index. Likewise, CRC patients were characterized by a specific enrichment of VAT-associated NKT-like cells. In addition, Ob and CRC-affected individuals shared a significant reduction of the V γ 9V δ 2/ γδ T cell ratio at systemic level. The alterations in the relative proportions of T reg and NKT-like cells in VAT were found to correlate with the content of pro- and anti-inflammatory polyunsaturated fatty acids (PUFA), respectively. Overall, these results provide evidence for distinct alterations of the immune cell repertoire in the periphery with respect to the VAT microenvironment that uniquely characterize or are shared by different inflammatory conditions, such as obesity and CRC, and suggest that VAT PUFA composition may represent one of the factors that contribute to shape the immune phenotypes

Endogenous CCL2 neutralization restricts HIV-1 replication in primary human macrophages by inhibiting viral DNA accumulation

Macrophages are key targets of HIV-1 infection. We have previously described that the expressionof CC chemokine ligand 2 (CCL2) increases during monocyte differentiation to macrophages and it is furtherup-modulated by HIV-1 exposure. Moreover, CCL2 acts as an autocrine factor that promotes viral replication ininfected macrophages. In this study, we dissected the molecular mechanisms by which CCL2 neutralization inhibitsHIV-1 replication in monocyte-derived macrophages (MDM), and the potential involvement of the innate restrictionfactors protein sterile alpha motif (SAM) histidine/aspartic acid (HD) domain containing 1 (SAMHD1) and apolipoproteinB mRNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) family members.Results:CCL2 neutralization potently reduced the number of p24 Gag+cells during the course of either productive orsingle cycle infection with HIV-1. In contrast, CCL2 blocking did not modify entry of HIV-1 based Virus Like Particles, thusdemonstrating that the restriction involves post-entry steps of the viral life cycle. Notably, the accumulation of viralDNA, both total, integrated and 2-LTR circles, was strongly impaired by neutralization of CCL2. Looking for correlates ofHIV-1 DNA accumulation inhibition, we found that the antiviral effect of CCL2 neutralization was independent of themodulation of SAMHD1 expression or function. Conversely, a strong and selective induction of APOBEC3A expression,to levels comparable to those of freshly isolated monocytes, was associated with the inhibition of HIV-1 replicationmediated by CCL2 blocking. Interestingly, the CCL2 neutralization mediated increase of APOBEC3A expression was typeI IFN independent. Moreover, the transcriptome analysis of the effect of CCL2 blocking on global gene expressionrevealed that the neutralization of this chemokine resulted in the upmodulation of additional genes involved in thedefence response to viruses.Conclusions:Neutralization of endogenous CCL2 determines a profound restriction of HIV-1 replication in primaryMDM affecting post-entry steps of the viral life cycle with a mechanism independent of SAMHD1. In addition, CCL2blocking is associated with induction of APOBEC3A expression, thus unravelling a novel mechanism which mightcontribute to regulate the expression of innate intracellular viral antagonistsin vivo. Thus, our study may potentially leadto the development of new therapeutic strategies for enhancing innate cellular defences against HIV-1 and protecting macrophages from infection

Gender-related differences in lifestyle may affect health status

Consistent epidemiological and clinical evidence strongly indicates that chronic noncommunicable diseases are largely associated with four lifestyle risk factors: inadequatediet, physical inactivity, tobacco use, and excessive alcohol use. Notably, obesity, a worldwide-growing pathological condition determined by the combination between inadequate diet and insufficient physical activity, is now considered a main risk factor for most chronic diseases. Dietary habits and physical activity are strongly influenced by gender attitudes and behaviors that promote different patterns of healthy or unhealthy lifestyles among women and men. Furthermore, different roles and unequal relations between genders strongly interact with differences in social and economic aspects as well as cultural and societal environment. Because of the complex network of factors involved in determining the risk for chronic diseases, it has been promoting a systemic approach that, by integrating sex and gender analysis, explores how sex-specific biological factors and gender-related social factors can interact to influence the health status