Molecular mechanisms of repeated social defeat-induced glucocorticoid resistance: Role of microRNA

Glucocorticoid (GC) resistance is a severe problem associated with various inflammatory diseases. Previous studies have shown that repeated social stress induces GC resistance in innate immune cells, but the underlying molecular mechanisms have not been fully elucidated. Therefore, the purpose of this study was to examine potential underlying molecular mechanism(s) of repeated social defeat (RSD) stress on GC resistance in splenic macrophages. It was hypothesized that mRNA expression of receptors for GC and nuclear translocating-associated regulators in splenic macrophages would be affected by RSD, and that these changes would be associated with epigenetic modification. The data showed that the mRNA expression of GC and mineralocorticoid receptors were significantly decreased in splenic macrophages by RSD. RSD also induced a significantly decreased mRNA expression in FK506-binding protein 52 (FKBP52), consequently resulting in a significantly increased ratio of FKBP51 to FKBP52. Moreover, DNA methyltransferases 3a and 3b showed a significant decrease in their mRNA expression in the RSD group as did mRNA expression of histone deacetyltransferase 2. The RSD group also showed a significantly reduced quantity of methylated DNA in splenic macrophages. Based on microRNA (miRNA) profiling data, it was determined that RSD induced significantly increased expression of 9 different miRNAs that were predicted to interact with mRNAs of the GC receptor (6 miRNAs), mineralocorticoid receptor (3 miRNAs) and FKBP52 (2 miRNAs). Spearman correlation analysis revealed significantly strong correlations between the expression of 2 miRNAs and their target mRNA expression for GC receptors. Among these miRNAs, we verified direct effects of miRNA-29b and -340 overexpression on mRNA expression of GC receptors in L929 cells. The overexpression of miRNA-29b or -340 in L929 cells significantly reduced LPS-induced overexpression of GC receptors. In conclusion, this study provides evidence that epigenetic regulation, such as DNA methylation and miRNA expression, may play a role in the RSD-induced GC resistance that we have observed in splenic macrophages.     

Helminth Antigen Exposure Enhances Early Immune Control of Mycobacterium tuberculosis in Monocytes and Macrophages

Helminth and Mycobacterium tuberculosis (Mtb) coinfection is common and suggested to influence the risk of developing active tuberculosis (TB). It is known that helminths in contrast to TB induce a strong Th2 response in the host. However, the direct impact of helminth antigen exposure on host immunity against TB is largely unknown. Our aim was to explore the effects of helminth antigen exposure on the early immune control of Mtb in monocytes and macrophages. Ascaris lumbricoides (ASC) and Schistosoma mansoni (SM) protein antigens were used to study the immediate effect of helminth antigen exposure in monocytes, on monocyte-to-macrophage differentiation, or mature macrophages, in the control of virulent Mtb H37Rv. Pre-exposure of peripheral blood mononuclear cells reduced Mtb growth in monocytes, especially with SM, but no Th1/Th2 cytokines or activation markers indicated involvement of T cells. Monocytes exposed before maturing into macrophages reduced Mtb growth in macrophages (ASC), and pre-exposure of mature macrophages reduced (ASC) or kept Mtb growth at control levels (SM). This in vitro model shows how helminth infection directly affects the monocyte-macrophage axis at an early stage before cell-mediated immunity develops. During acute helminth coinfection or when helminth antigen concentration is elevated at the site of Mtb infection, these helminths provide an enhanced control and killing of Mtb owing to the direct stimulatory effect of helminth antigens on phagocytic cells.     

Inflammatory status in human hepatic cirrhosis

This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus(HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcoholinduced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis(HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared withHCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gutmesenteric lymph nodes-peritoneal-systemic axis.     

Convergent pathways of macrophage polarization: The role of B cells

The construction of an inflammatory microenvironment provides the fuel for cancer development and progression. Hence, solid tumors promote infiltration of leukocyte populations, among which tumor‐associated macrophages (TAM) represent a paradigm for cancer‐promoting inflammation. TAM orchestrate various aspects of cancer, including diversion and skewing of adaptive responses, cell growth, angiogenesis, matrix deposition and remodelling, the construction of a metastatic niche and actual metastasis, response to hormones and chemotherapeutic agents. Several lines of evidence indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, suggesting that during tumor progression macrophages undergo a phenotypic “switch”, eventually exhibiting the alternatively activated, “M2”, phenotype that is associated with immunosuppression, promotion of tumor angiogenesis and metastasis. Although recent studies have attempted to address the role of microenvironmental signals on TAM “reprogramming”, the interplay between innate and adaptive immunity is emerging as a crucial step of this event. In this issue of the European Journal of Immunology, a study demonstrates that B1 lymphocytes expressing IL‐10 play a key role in promoting a pro‐tumoral M2‐biased phenotype of macrophages. This article defines a new in vivo pathway of macrophage polarization and suggests that targeting B cells is a possible therapeutic intervention to reinstate anti‐cancer functions by TAM.     

The role of macrophages and mast cells in lymphangiogenesis and angiogenesis in cervical carcinogenesis

During carcinogenesis it is known that growth factors and cytokines from stromal and inflammatory cells from the microenvironment promote angiogenesis and lymphangiogenesis. However, the participation of macrophages and mast cells in these processes is not well understood. The aim of this study was to evaluate the relationship between mast cell and macrophage density with blood and lymphatic vessels in various stages of carcinoma of the uterine cervix. Tissue sections from archival paraffin-embedded samples from cases with cervical intraepithelial neoplasias (CIN) 1, 2, 3, carcinoma in situ, and invasive carcinoma were used. Immunohistochemical staining was done using the following antibodies: anti-LYVE-1; anti-CD31; anti-CD68, and anti-tryptase. Our results showed a significant increase in the number of macrophages in carcinoma in situ, a correlation between lymphatic vessels and macrophages in premalignant lesions CIN 2, and a correlation between mast cells and blood vessels in both CIN 2 and carcinoma in situ. In conclusion, our data underscore the importance of the recruitment of macrophages and mast cells in the development of tumor-associated blood and lymphatic capillaries.     

Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma

Surgical resection of tumors is often followed by regrowth at the primary site and metastases may emerge rapidly following removal of the primary tumor. Macrophages are important drivers of tumor growth, and here we investigated their involvement in postoperative relapse as well as explore macrophage depletion as an adjuvant to surgical resection. RETAAD mice develop spontaneous metastatic melanoma that begins in the eye. Removal of the eyes as early as 1 week of age did not prevent the development of metastases; rather, surgery led to increased proliferation of tumor cells locally and in distant metastases. Surgery-induced increase in tumor cell proliferation correlated with increased macrophage density within the tumor. Moreover, macrophages stimulate tumor sphere formation from tumor cells of post-surgical but not control mice. Macrophage depletion with a diet containing the CSF-1R specific kinase inhibitor Ki20227 following surgery significantly reduced postoperative tumor recurrence and abrogated enhanced metastatic outgrowth. Our results confirm that tumor cells disseminate early, and show that macrophages contribute both to post-surgical tumor relapse and growth of metastases, likely through stimulating a population of tumor-initiating cells. Thus macrophage depletion warrants exploration as an adjuvant to surgical resection.     

Catestatin decreases macrophage function in two mouse models of experimental colitis

Mucosal inflammation in patients with inflammatory bowel disease (IBD) is characterized by an alteration of prohormone chromogranin A (CgA) production. The recent demonstration of an implication of CgA in collagenous colitis and immune regulation provides a potential link between CgA-derived peptides (catestatin, CTS) and gut inflammation.     

Extracellular matrix turnover and signaling during cardiac remodeling following MI: Causes and consequences

The concept that extracellular matrix (ECM) turnover occurs during cardiac remodeling is a well-accepted paradigm. To date, a multitude of studies document that remodeling is accompanied by increases in the synthesis and deposition of ECM components as well as increases in extracellular proteases, especially matrix metalloproteinases (MMPs), which break down ECM components. Further, soluble ECM fragments generated from enzymatic action serve to stimulate cell behavior and have been proposed as candidate plasma biomarkers of cardiac remodeling. This review briefly summarizes our current knowledge base on cardiac ECM turnover following myocardial infarction (MI), but more importantly extends discussion by defining avenues that remain to be explored to drive the ECM remodeling field forward. Specifically, this review will discuss cause and effect roles for the ECM changes observed following MI and the potential role of the ECM changes that may serve as trigger points to regulate remodeling. While the pattern of remodeling following MI is qualititatively similar but quantitively different from various types of injury, the basic theme in remodeling is repeated. Therefore, while we use the MI model as the prototype injury model, the themes discussed here are also relevant to cardiac remodeling due to other types of injury.     

Neutrophils,but Not Lymphocytes or Monocytes,Infiltrate Maternal Systemic Vasculature in Women with Preeclampsia

Objective: Leukocytes are activated in women with preeclampsia, but the class of leukocytes that infiltrates the maternal vasculature and, therefore, is most likely to cause vascular dysfunction is not known. Methods: Subcutaneous fat biopsies were obtained at Cesarean section or abdominal surgery from 7 normal non-pregnant women, 7 women with normal pregnancies, and 7 women with preeclampsia. Tissues were immunohistochemically stained for CD14, a monocyte/macrophage antigen, CD99, a lymphocyte antigen, and CD66b, a neutrophil antigen. Results: CD14 stained cells were found infiltrated into fat tissue but were not present in vessels for any of the groups. CD99-stained cells were present in approximately 20% to 30% of vessels with no difference among groups. CD66b-stained cells were present in all groups with a significantly greater percentage of vessels stained for preeclamptic than normal pregnant or normal non-pregnant women (70 ± 6 vs. 43 ± 9 vs. 21 ± 5%, respectively, p < 0.01). CD66b cells were the most abundant cell type that infiltrated vessels of preeclamptic women. Conclusions: 1) A significantly greater number of neutrophils adhered to endothelium and infiltrated into the intimal space in the maternal systemic vasculature of preeclamptic women than in that of normal pregnant women or normal non-pregnant women; 2) No significant difference in lymphocyte infiltration was observed among the patient groups, and lymphocytes were present in much lower numbers than-neutrophils; 3) Monocytes/macrophages were found in fat tissue but not in vessels. We speculate that neutrophils are the class of leukocytes that cause the majority of vascular cell dysfunction in women with preeclampsia.