Fibrocytes: Bringing new insights into mechanisms of inflammation and fibrosis

Regeneration and fibrosis are integral parts of the recovery process following tissue injury, and impaired regulation of these mechanisms is a hallmark of many chronic diseases. A population of bone marrow-derived mesenchymal progenitor cells known as fibrocytes, play an important role in tissue remodeling and fibrosis in both physiologic and pathologic settings. In this review we summarize the key concepts regarding the pathophysiology of wound healing and fibrosis, and present data to support the contention that circulating fibrocytes are important in both normal repair process and aberrant healing and fibrotic damage associated with a diverse set of disease states.     

Cytokines: IL-20 - a new effector in skin inflammation

The newly discovered cytokine interleukin-20 (IL-20) is structurally related to IL-10, yet it appears to be an autocrine factor for keratinocytes that regulates their participation in inflammation.     

Regenerative potential of human muscle stem cells in chronic inflammation

Introduction

Chronic inflammation is a profound systemic modification of the cellular microenvironment which could affect survival, repair and maintenance of muscle stem cells. The aim of this study was to define the role of chronic inflammation on the regenerative potential of satellite cells in human muscle.

Methods

As a model for chronic inflammation, 11 patients suffering from rheumatoid arthritis (RA) were included together with 16 patients with osteoarthritis (OA) as controls. The mean age of both groups was 64 years, with more females in the RA group compared to the OA group. During elective knee replacement surgery, a muscle biopsy was taken from the distal musculus vastus medialis. Cell populations from four RA and eight OA patients were used for extensive phenotyping because these cell populations showed no spontaneous differentiation and myogenic purity greater than 75% after explantation.

Results

After mononuclear cell explantation, myogenic purity, viability, proliferation index, number of colonies, myogenic colonies, growth speed, maximum number of population doublings and fusion index were not different between RA and OA patients. Furthermore, the expression of proteins involved in replicative and stress-induced premature senescence and apoptosis, including p16, p21, p53, hTERT and cleaved caspase-3, was not different between RA and OA patients. Mean telomere length was shorter in the RA group compared to the OA group.

Conclusions

In the present study we found evidence that chronic inflammation in RA does not affect the in vitro regenerative potential of human satellite cells. Identification of mechanisms influencing muscle regeneration by modulation of its microenvironment may, therefore, be more appropriate.     

Salmonella type III effector AvrA stabilizes cell tight junctions to inhibit inflammation in intestinal epithelial cells

Salmonella Typhimurium is a major cause of human gastroenteritis. The Salmonella type III secretory system secretes virulence proteins, called effectors. Effectors are responsible for the alteration of tight junction (TJ) structure and function in intestinal epithelial cells. AvrA is a newly described bacterial effector found in Salmonella. We report here that AvrA expression stabilizes cell permeability and tight junctions in intestinal epithelial cells. Cells colonized with an AvrA-deficient bacterial strain (AvrA-) displayed decreased cell permeability, disruption of TJs, and an increased inflammatory response. Western blot data showed that TJ proteins, such as ZO-1, claudin-1, decreased after AvrA- colonization for only 1 hour. In contrast, cells colonized with AvrA-sufficient bacteria maintained cell permeability with stabilized TJ structure. This difference was confirmed in vivo. Fluorescent tracer studies showed increased fluorescence in the blood of mice infected with AvrA- compared to those infected with the AvrA-sufficient strains. AvrA- disrupted TJ structure and function and increased inflammation in vivo, compared to the AvrA- sufficient strain. Additionally, AvrA overexpression increased TJ protein expression when transfected into colonic epithelial cells. An intriguing aspect of this study is that AvrA stabilized TJs, even though the other TTSS proteins, SopB, SopE, and SopE2, are known to disrupt TJs. AvrA may play a role in stabilizing TJs and balancing the opposing action of other bacterial effectors. Our findings indicate an important role for the bacterial effector AvrA in regulation of intestinal epithelial cell TJs during inflammation. The role of AvrA represents a highly refined bacterial strategy that helps the bacteria survive in the host and dampen the inflammatory response.     

How bacteria initiate inflammation: aspects of the emerging story

Recent studies have shown that bacteria possess an array of proinflammatory molecules in addition to the extensively studied lipopolysaccharide and superantigens. These bacterial molecules include soluble and membrane-associated inducers of cytokine release, inducers of host cell apoptosis, and immunostimulatory DNA. There is therefore much greater diversity in the class of molecules and mechanisms by which bacteria engage the host immune system than previously appreciated.     

Lymphocytotoxicity in alcoholic hepatitis: evalutation of effector cells

Alcohol induced liver damage has been recently suggested to occur in some cases as a consequence of a true autoimmune reaction. However the nature of the effector cells is still debated. Microlymphocytotoxicity "in vitro" test against rabbit hepatocytes has been performed in 29 patients with alcoholic cirrhosis and 8 with acute alcoholic hepatitis. The diagnosis has been done on clinical and histological grounds. The mean cytotoxicity index (CI) of subjects with alcoholic cirrhosis was 15.12 +/- 14.18 and with acute alcoholic hepatitis 62.49 +/- 16.33 (normal range: 0 -37.90). To further characterize the effector cells in our system, the test has been performed again either using T-enriched fractions of peripheral lymphocytes or after pronase-induced digestion of SmIg of total lymphocytes in 5 patients with acute alcoholic hepatitis and high CI. In both instances a disappearance of citotoxic activity has been observed. These data suggest: a) autoimmune reaction can occur only in patients with acute alcoholic liver damage; b) non T-cells are responsible for cytotoxicity; c) the immune reaction appears to be of cell-mediated antibody-dependent type.     

The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema

Induction of a chronic eczema is a most efficient therapy for alopecia areata (AA). We had noted a reduction in regulatory T cells during AA induction and wondered whether regulatory T cells may become recruited or expanded during repeated skin sensitization or whether additional regulatory cells account for hair regrowth. AA could not be cured by the transfer of CD4(+)CD25(high) lymph node cells from mice repeatedly treated with a contact sensitizer. This obviously is a consequence of a dominance of freshly activated cells as compared with regulatory CD4(+)CD25(+) T cells. Instead, a population of Gr-1(+)CD11b(+) cells was significantly increased in skin and spleen of AA mice repeatedly treated with a contact sensitizer. Gr-1(+)CD11b(+) spleen cells mostly expressed CD31. Expression of several proinflammatory cytokines as well as of the IFN-gamma receptor and the TNF receptor I were increased. Particularly in the skin, Gr-1(+) cells expressed several chemokines and CCR8 at high levels. Gr-1(+)CD11b(+) cells most potently suppressed AA effector cell proliferation in vitro and promoted partial hair regrowth in vivo. When cocultured with CD4(+) or CD8(+) cells from AA mice, the Gr-1(+)CD11b(+) cells secreted high levels of NO. However, possibly due to high level Bcl-2 protein expression in AA T cells, apoptosis induction remained unaltered. Instead, zeta-chain expression was strongly down-regulated, which was accompanied by a decrease in ZAP70 and ERK1/2 phosphorylation. Thus, a chronic eczema supports the expansion and activation of myeloid suppressor cells that, via zeta-chain down-regulation, contribute to autoreactive T cell silencing in vitro and in vivo.     

The effector cells and cellular mediators of immune system involved in cardiac inflammation and fibrosis after myocardial infarction

The cardiac repair after myocardial infarction (MI) involves two phases, namely, inflammatory response and proliferative response. The former is an inflammatory reaction, evoked by different kinds of pro-inflammatory leukocytes and molecules stimulated by myocardial necrosis, while the latter is a repair process, predominated by a magnitude of anti-inflammatory cells and cytokines, as well as fibroblasts. Cardiac remodeling post-MI is dependent on the balance of individualized intensity of the post-MI inflammation and subsequent cardiac fibrosis. During the past 30 years, enormous studies have focused on investigating immune cells and mediators involved in cardiac inflammation and fibrosis, which are two interacting processes of post-MI cardiac repair. These results contribute to revealing the mechanism of adverse cardiac remodeling after MI and alleviating the impairment of cardiac function. In this study, we will broadly discuss the role of immune cell subpopulation and the involved cytokines and chemokines during cardiac repair post-MI, particular in cardiac inflammation and fibrosis.     

Osteocalcin does not influence acute or chronic inflammation in human vascular cells

Some human observational studies have suggested an anti-inflammatory role of osteocalcin (OCN). An inflammatory protocol using interferon-γ and tumor necrosis factor-α (10 ng/ml) was employed to examine the acute (24 hr) and chronic (144 hr) effects of uncarboxylated OCN (ucOCN) in commercial, primary, subcultured human aortic endothelial cells (HAEC), and human smooth muscle cells (HASMCs). The inflammatory protocol increased phosphorylation of intracellular signaling proteins (CREB, JNK, p38, ERK, AKT, STAT3, STAT5) and increased secretion of adhesion markers (vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1) and proinflammatory cytokines (interleukin-6 [IL-6], IL-8). After acute inflammation, there were no additive or reductive effects of ucOCN in either cell type. Following chronic inflammation, ucOCN did not affect cell responses, nor did it appear to have any pro- or anti-inflammatory effects when administered acutely or chronically on its own in either cell type. Additionally, ucOCN did not affect lipopolysaccharide (LPS)-induced acute inflammation in HAECs or HASMCs. The findings of this study do not support a causal role for OCN within the models of vascular inflammation chosen. Further confirmatory studies are warranted.     

Iron homeostasis in chronic inflammation

Inflammation induced anemia and resistance to erythropoietin are common features in patients with chronic kidney disease (CKD). Elevated levels of cytokines and enhanced oxidative stress, conditions associated with inflammatory states, are implicated in the development of anemia. Accumulating evidence suggests that activation of cytokine cascade and the associated acute-phase response, as it often occurs in patients with CKD, divert iron from erythropoiesis to storage sites within the reticuloendothelial system leading to functional iron deficiency and subsequently to anemia or resistance to erythropoietin. Other processes have also been shown to be involved in the pathogenesis of anemia provoked by the activated immune system including an inhibition of erythroid progenitor proliferation and differentiation, a suppression of erythropoietin production and a blunted response to erythropoietin. The present review concerns the underlying alterations in iron metabolism induced by chronic inflammation that result in anemia.     

Fibrocytes and the tissue niche in lung repair

Human fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of markers related to leukocytes, hematopoietic stem cells and a diverse set of fibroblast phenotypes. Fibrocytes can be recruited from the circulation to the tissue where they further can differentiate and proliferate into various mesenchymal cell types depending on the tissue niche. This local tissue niche is important because it modulates the fibrocytes and coordinates their role in tissue behaviour and repair. However, plasticity of a niche may be co-opted in chronic airway diseases such as asthma, idiopathic pulmonary fibrosis and obliterative bronchiolitis. This review will therefore focus on a possible role of fibrocytes in pathological tissue repair processes in those diseases.     

循环纤维细胞及其在肺纤维化中的作用

循环纤维细胞(crculating fibrocytes CF)是一类骨髓来源的间质性细胞,可以同时表达造血细胞、单核细胞和成纤维细胞系的细胞标记。现有越来越多动物实验证据表明,CF的分化、转移功能在慢性炎症反应和胶原过度沉积中起着重要作用。近年来的实验表明,对CF的计数可以作为纤维化类疾病发展过程中的生物标记物,尤其在肺纤维化中更加明显。特发性肺纤维化是一种慢性肺部功能失调疾病,确诊后病人5年生存率低于30%。特发性肺纤维化是一种慢性肺部功能失调疾病,确诊后病人5年生存率低于30%。传统的免疫学疗法疗效很差。最近人们开始把注意力集中到对始祖干细胞的免疫调节机制上来。随着对循环纤维细胞研究的不断深入,对特发性纤维化的发病原因以及治疗研究方面有了较大发展。     

Targeting the silent minority: emerging immunotherapeutic strategies for eradication of malignant stem cells in chronic myeloid leukaemia

Standard allogeneic stem cell transplantation (alloSCT) has provided a cure for chronic myeloid leukaemia (CML) over the last 25 years, but is only an option for a minority of patients. It was hoped that the introduction of imatinib mesylate (IM), a specific tyrosine kinase inhibitor that targets the Bcr-Abl oncogene product, would provide long-term remission or even cure for those patients without a donor, but studies have shown that IM does not eliminate leukaemic stem cells in CML patients. To overcome this problem of molecular persistence, research is underway to combine reduced intensity stem cell transplant or non-donor-dependent immunotherapies with IM with the aim of increasing cure rate, reducing toxicity and improving quality of life. The alternative approach is to combine IM or second-generation agents with other novel drugs that interrupt key signalling pathways activated by Bcr-Abl. This article will focus on the latest immunotherapy and molecularly targeted therapeutic options in CML and how they may be combined to improve the outcome for CML patients in the future.     

循环纤维细胞及其在肺纤维化中的作用

循环纤维细胞（circulating fibrocytes CF）是一类骨髓来源的间质性细胞,可以同时表达造血细胞、单核细胞和成纤维细胞系的细胞标记。现有越来越多动物实验证据表明,CF的分化、转移功能在慢性炎症反应和胶原过度沉积中起着重要作用。近年来的实验表明,对CF的计数可以作为纤维化类疾病发展过程中的生物标记物,尤其在肺纤维化中更加明显。特发性肺纤维化是一种慢性肺部功能失调疾病,确诊后病人5年生存率低于30％。特发性肺纤维化是一种慢性肺部功能失调疾病,确诊后病人5年生存率低于30％。传统的免疫学疗法疗效很差。最近人们开始把注意力集中到对始祖干细胞的免疫调节机制上来。随着对循环纤维细胞研究的不断深入,对特发性纤维化的发病原因以及治疗研究方面有了较大发展。     

Mouse mast cells as anti-tumor effector cells

Mast cells were obtained in a high state of purity from mouse peritoneal washings by means of centrifugation over metrizamide density gradients. In microcytotoxicity assays in vitro they were cytotoxic to cells of a mouse methylcholanthrene-induced fibrosarcoma (C-4). Mast cells from uninjected mice, mice injected intraperitoneally with proteose peptone, and C-4-bearing mice were equally effective. They were also cytotoxic to two rat fibrosarcomas and, to a much lesser extent, to mouse fibroblasts. Cytotoxicity was inhibited by cAMP, DBcAMP, and reserpine but not by chloroquin, hydrocortisone, chlorpheniramine, promethazine, cimetidine, sodium cromoglycate, protamine sulfate, cytochalasin B, or colchicine.     

Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation

Transplanted bone marrow-derived cells (BMDCs) have been reported to fuse with cells of diverse tissues, but the extremely low frequency of fusion has led to the view that such events are biologically insignificant. Nonetheless, in mice with a lethal recessive liver disease (tyrosinaemia), transplantation of wild-type BMDCs restored liver function by cell fusion and prevented death, indicating that cell fusion can have beneficial effects. Here we report that chronic inflammation resulting from severe dermatitis or autoimmune encephalitis leads to robust fusion of BMDCs with Purkinje neurons and formation of hundreds of binucleate heterokaryons per cerebellum, a 10-100-fold higher frequency than previously reported. Single haematopoietic stem-cell transplants showed that the fusogenic cell is from the haematopoietic lineage and parabiosis experiments revealed that fusion can occur without irradiation. Transplantation of rat bone marrow into mice led to activation of dormant rat Purkinje neuron-specific genes in BMDC nuclei after fusion with mouse Purkinje neurons, consistent with nuclear reprogramming. The precise neurological role of these heterokaryons awaits elucidation, but their frequency in brain after inflammation is clearly much higher than previously appreciated.