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Type 2 inflammation is a defining feature of infection with parasitic worms(helminths), as well as being responsible for widespread suffering in allergies.However, the precise mechanisms involved in T helper (Th) 2 polarization bydendritic cells (DCs) are currently unclear. We have identified a previouslyunrecognized role for type I IFN (IFN-I) in enabling this process. An IFN-Isignature was evident in DCs responding to the helminth Schistosomamansoni or the allergen house dust mite (HDM). Further, IFN-I signaling wasrequired for optimal DC phenotypic activation in response to helminth antigen(Ag), and efficient migration to, and localization with, T cells in the draininglymph node (dLN). Importantly, DCs generated from Ifnar1-/- mice wereincapable of initiating Th2 responses in vivo. These data demonstrate for thefirst time that the influence of IFN-I is not limited to antiviral or bacterialsettings but also has a central role to play in DC initiation of Th2 responses.

Macrophage cell fusion and multinucleation are fundamental processes in the formation of multinucleated giant cells (MGCs) in chronic inflammatory disease and osteoclasts in the regulation of bone mass. However, this basic cell phenomenon is poorly understood despite its pathophysiological relevance. Granulomas containing multinucleated giant cells are seen in a wide variety of complex inflammatory disorders, as well as in infectious diseases. Dysregulation of osteoclastic bone resorption underlies the pathogenesis of osteoporosis and malignant osteolytic bone disease. Recent reports have shown that the formation of multinucleated giant cells and osteoclast fusion display a common molecular signature, suggesting shared genetic determinants. In this Review, we describe the background of cell–cell fusion and the similar origin of macrophages and osteoclasts. We specifically focus on the common pathways involved in osteoclast and MGC fusion. We also highlight potential approaches that could help to unravel the core mechanisms underlying bone and granulomatous disorders in humans.

Mycobacterium tuberculosis can proficiently enter phagocytes and diminish complement 23 activation on its cell surface. Within phagocytes, the mycobacterium can suppress 24 macrophage apoptosis and survive the intracellular environment. Complement regulatory 25 proteins such as factor H may facilitate pathogen-macrophage interactions during 26 tuberculosis infection. In this study, we show that M. bovis BCG binds properdin, an up27 regulator of the complement alternative pathway. TSR4+5, a recombinant form of 28 thrombospondin repeats 4 and 5 of human properdin expressed in tandem, which is an 29 inhibitor of the alternative pathway, was also able to bind M. bovis BCG. Properdin and 30 TSR4+5 were found to inhibit uptake of M. bovis BCG by THP-1 macrophage cells in a 31 dose-dependent manner. Quantitative real-time PCR assays using transcripts from the THP-1 32 cells revealed elevated pro-inflammatory responses (TNF-α, IL-1β and IL-6) in the presence 33 of properdin and TSR4+5, which gradually decreased over 6 hours. Correspondingly, anti34 inflammatory responses (IL-10, TGF-β and IL-12) showed suppressed levels of expression in 35 the presence of properdin, which gradually increased over 6 hours. Multiplex cytokine array 36 analysis further revealed that properdin and TSR4+5 significantly enhanced the pro37 inflammatory response (TNF-α, IL-1β and IL-1α) at 24 hours, which declined at 48 hours, 38 whereas the anti-inflammatory response (IL-10 and IL-12) was suppressed. Our results 39 suggest that properdin may interfere with mycobacterial entry into macrophages involving 40 TSR4 and TSR5, particularly during the initial stages of infection, thus, affecting the 41 extracellular survival of the pathogen. This study offers novel insights into non-complement 42 related functions of properdin, which may be independent of other complement proteins 43 during host-pathogen interactions in tuberculosis. Thus, human properdin modulates 44 macrophage-M. bovis BCG interaction via TSR4+5. Properdin residing in the granules of 45 neutrophils is secreted upon stimulation and may also be produced by other cell types such as 3 monocytes, bone marrow progenitor cell lines and T cells. The local production 46 of properdin 47 may be crucial for recruitment at sites of infection and in the control of M. tuberculosis 48 infection.

Macrophages provide front line defense against infections. The study of macrophage–microbe interplay is thus crucial for understanding pathogenesis and infection control. Zebrafish (Danio rerio) larvae provide a unique platform to study macrophage–microbe interactions in vivo, from the level of the single cell to the whole organism. Studies using zebrafish allow non-invasive, real-time visualization of macrophage recruitment and phagocytosis. Furthermore, the chemical and genetic tractability of zebrafish has been central to decipher the complex role of macrophages during infection. Here, we discuss the latest developments using zebrafish models of bacterial and fungal infection. We also review novel aspects of macrophage biology revealed by zebrafish, which can potentiate development of new therapeutic strategies for humans.

Background Symptomatic acute schistosomiasis mansoni is a systemic hypersensitivity reaction against the migrating schistosomula and mature eggs after a primary infection. The mechanisms involved in the pathogenesis of acute schistosomiasis are not fully elucidated. Osteopontin has been implicated in granulomatous reactions and in acute hepatic injury. Our aims were to evaluate if osteopontin plays a role in acute Schistosoma mansoni infection in both human and experimentally infected mice and if circulating OPN levels could be a novel biomarker of this infection. Methodology/Principal Findings Serum/plasma osteopontin levels were measured by ELISA in patients with acute (n = 28), hepatointestinal (n = 26), hepatosplenic (n = 39) schistosomiasis and in uninfected controls (n = 21). Liver osteopontin was assessed by immunohistochemistry in needle biopsies of 5 patients. Sera and hepatic osteopontin were quantified in the murine model of schistosomiasis mansoni during acute (7 and 8 weeks post infection, n = 10) and chronic (30 weeks post infection, n = 8) phase. Circulating osteopontin levels are increased in patients with acute schistosomiasis (p = 0.0001). The highest levels of OPN were observed during the peak of clinical symptoms (7–11 weeks post infection), returning to baseline level once the granulomas were modulated (>12 weeks post infection). The plasma levels in acute schistosomiasis were even higher than in hepatosplenic patients. The murine model mirrored the human disease. Macrophages were the major source of OPN in human and murine acute schistosomiasis, while the ductular reaction maintains OPN production in hepatosplenic disease. Soluble egg antigens from S. mansoni induced OPN expression in primary human kupffer cells. Conclusions/Significance S. mansoni egg antigens induce the production of OPN by macrophages in the necrotic-exudative granulomas characteristic of acute schistosomiasis mansoni. Circulating OPN levels are upregulated in human and murine acute schistosomiasis and could be a non-invasive biomarker of this form of disease., Author Summary Schistosomiasis is a major health problem that affects over 200 million people. Symptomatic acute schistosomiasis is a systemic reaction to the worms and eggs in individuals from non-endemic areas after a primary infection. Tourists, military personnel and people who practice water sports are at risk. Although most cases resolve 90 days post infection, severe cases with massive distribution of eggs can be fatal. It is frequently misdiagnosed, under diagnosed or has delayed diagnosis because the signs and symptoms are nonspecific and eggs are usually present in stool only 6 weeks post-infection. The mechanisms underlying the pathogenesis of acute schistosomiasis are not fully elucidated and currently there is a lack of noninvasive biomarkers to diagnose this form of disease. We report that serum osteopontin levels are increased in patients with acute schistosomiasis and parallel the clinical symptoms, returning to baseline level once the granulomas were modulated and the symptoms resolve. Soluble egg antigens provoke macrophages to produce osteopontin, recruiting more macrophages to the site of injury and inducing the granulomatous reaction. This observation suggests that osteopontin plays an important role in acute schistosomiasis mansoni and could be a novel non-invasive biomarker for this form of the disease.

International audience; The growth of Mycobacterium tuberculosis mutants unable to synthesize phthiocerol dimycocerosates (DIMs) was recently shown to be impaired in mouse lungs. However, the precise role of these molecules in the course of infection remained to be determined. Here, we provide evidence that the attenuation of a DIM-deficient strain takes place during the acute phase of infection in both lungs and spleen of mice, and that this attenuation results in part from the increased sensitivity of the mutant to the cidal activity of reactive nitrogen intermediates released by activated macrophages. We also show that the DIM-deficient mutant, the growth and survival of which were not impaired within resting macrophages and dendritic cells, induced these cells to secrete more tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 than the wild-type strain. Although purified DIM molecules by themselves had no effect on the activation of macrophages and dendritic cells in vitro, we found that the proper localization of DIMs in the cell envelope of M. tuberculosis is critical to their biological effects. Thus, our findings suggest that DIM production contributes to the initial growth of M. tuberculosis by protecting it from the nitric oxide-dependent killing of macrophages and modulating the early immune response to infection.

The recruitment of leukocytes to infectious foci depends strongly on the local release of chemoattractant mediators. The human CXC chemokine receptor 3 (CXCR3) is an important node in the chemokine signaling network and is expressed by multiple leukocyte lineages, including T cells and macrophages. The ligands of this receptor originate from an ancestral CXCL11 gene in early vertebrates. Here, we used the optically accessible zebrafish embryo model to explore the function of the CXCR3-CXCL11 axis in macrophage recruitment and show that disruption of this axis increases the resistance to mycobacterial infection. In a mutant of the zebrafish ortholog of CXCR3 (cxcr3.2), macrophage chemotaxis to bacterial infections was attenuated, although migration to infection-independent stimuli was unaffected. Additionally, attenuation of macrophage recruitment to infection could be mimicked by treatment with NBI74330, a high-affinity antagonist of CXCR3. We identified two infection-inducible CXCL11-like chemokines as the functional ligands of Cxcr3.2, showing that the recombinant proteins exerted a Cxcr3.2-dependent chemoattraction when locally administrated in vivo. During infection of zebrafish embryos with Mycobacterium marinum, a well-established model for tuberculosis, we found that Cxcr3.2 deficiency limited the macrophage-mediated dissemination of mycobacteria. Furthermore, the loss of Cxcr3.2 function attenuated the formation of granulomatous lesions, the typical histopathological features of tuberculosis, and led to a reduction in the total bacterial burden. Prevention of mycobacterial dissemination by targeting the CXCR3 pathway, therefore, might represent a host-directed therapeutic strategy for treatment of tuberculosis. The demonstration of a conserved CXCR3-CXCL11 signaling axis in zebrafish extends the translational applicability of this model for studying diseases involving the innate immune system.

Background Impaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis. Methods Patients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC). Results In sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO+ Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs - but not Th cells - showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs. Conclusion In untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients. Electronic supplementary material The online version of this article (doi:10.1186/s12931-015-0265-8) contains supplementary material, which is available to authorized users.

Mycobacterium ulcerans disease, also known as Buruli ulcer (BU), is a disease of subcutaneous fat tissue. BU is prevalent in riverine and swamp areas of the tropical zone in Africa, Asia and South America, and a few scattered foci in Australia. The mode of transmission of M. ulcerans has not been fully elucidated, but inoculation into the subcutaneous tissues probably occurs through penetrating skin trauma. BU has not been linked with HIV infection. Antimycobacterial drug treatment is ineffective, and treatment is surgical. Patients eventually develop scars and contractures, with resulting disabilities, and the disease imposes a large burden on affected populations. The incidence of BU has dramatically increased in West African countries over the last decade. There is an urgent need for research into host and environmental risk factors for BU in order to develop effective strategies to combat this disease. We review possible genetic host susceptibility factors for BU that are relevant in other mycobacterial diseases: natural resistance-associated macrophage protein-1 (NRAMP-1), HLA-DR, vitamin D3 receptor, mannose binding protein, interferon-gamma (IFN-gamma) receptor, tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-1 alpha, 1 beta and their receptor antagonists; and IL-12. Schistosoma haematobium infection is highly endemic in many BU foci in West Africa, with a striking increase in transmission after river dams were constructed. This observation, and the observations from interaction of schistosomiasis and tuberculosis, have fueled our hypothesis that schistosomiasis is a risk factor for BU by driving the host immune response towards a predominantly Th-2 pattern, away from a Th-1 preponderant protection against mycobacterial infection. If the latter hypothesis is confirmed, enhanced schistosomiasis control should impact on BU.

PURPOSE: Two young females with well-documented Crohn's disease and nonhealing perineal wounds following proctectomy compatible with "metastatic Crohn's disease" are described, We hypothesized that metastatic Crohn's disease would be a tumor necrosis factor-dependent inflammatory-reaction and have treated these two patients with the anti-tumor necrosis factor chimeric monoclonal antibody, cA2. MAIN FINDINGS: Administration of cA2 was followed by a rapid reduction of subjective and objective parameters of inflammation and caused a substantial reduction of the wound size, CONCLUSION: These preliminary data are consistent with a tumor necrosis factor-dependent inflammatory cause of Crohn's disease and its extraintestinal manifestations and provide support for targeting tumor necrosis factor in this condition.

Summary Mycobacterium tuberculosis-induced cellular aggregation is essential for granuloma formation and may assist establishment and early spread of M. tuberculosis infection. The M. tuberculosis ESX1 mutant, which has a non-functional type VII secretion system, induced significantly less production of the host macrophage-derived chemokine fractalkine (CX3CL1). Upon infection of human macrophages ESX1-dependent fractalkine production mediated selective recruitment of CD11b+ monocytic cells and increased infection of neighbouring cells consistent with early local spread of infection. Fractalkine levels were raised in vivo at tuberculous disease sites in humans and were significantly associated with increased CD11b+ monocytic cellular recruitment and extent of granulomatous disease. These findings suggest a novel fractalkine-dependent ESX1-mediated mechanism in early tuberculous disease pathogenesis in humans. Modulation of M. tuberculosis-mediated fractalkine induction may represent a potential treatment option in the future, perhaps allowing us to switch off a key mechanism required by the pathogen to spread between cells.

Mycobacterium ulcerans disease, also known as Buruli ulcer (BU), is a disease of subcutaneous fat tissue. BU is prevalent in riverine and swamp areas of the tropical zone in Africa, Asia and South America, and a few scattered foci in Australia. The mode of transmission of M. ulcerans has not been fully elucidated, but inoculation into the subcutaneous tissues probably occurs through penetrating skin trauma. BU has not been linked with HIV infection. Antimycobacterial drug treatment is ineffective, and treatment is surgical. Patients eventually develop scars and contractures, with resulting disabilities, and the disease imposes a large burden on affected populations. The incidence of BU has dramatically increased in West African countries over the last decade. There is an urgent need for research into host and environmental risk factors for BU in order to develop effective strategies to combat this disease. We review possible genetic host susceptibility factors for BU that are relevant in other mycobacterial diseases: natural resistance-associated macrophage protein-1 (NRAMP-1), HLA-DR, vitamin D3 receptor, mannose binding protein, interferon-gamma (IFN-gamma) receptor, tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-1 alpha, 1 beta and their receptor antagonists; and IL-12. Schistosoma haematobium infection is highly endemic in many BU foci in West Africa, with a striking increase in transmission after river dams were constructed. This observation, and the observations from interaction of schistosomiasis and tuberculosis, have fueled our hypothesis that schistosomiasis is a risk factor for BU by driving the host immune response towards a predominantly Th-2 pattern, away from a Th-1 preponderant protection against mycobacterial infection. If the latter hypothesis is confirmed, enhanced schistosomiasis control should impact on BU.

PURPOSE: Two young females with well-documented Crohn's disease and nonhealing perineal wounds following proctectomy compatible with "metastatic Crohn's disease" are described, We hypothesized that metastatic Crohn's disease would be a tumor necrosis factor-dependent inflammatory-reaction and have treated these two patients with the anti-tumor necrosis factor chimeric monoclonal antibody, cA2. MAIN FINDINGS: Administration of cA2 was followed by a rapid reduction of subjective and objective parameters of inflammation and caused a substantial reduction of the wound size, CONCLUSION: These preliminary data are consistent with a tumor necrosis factor-dependent inflammatory cause of Crohn's disease and its extraintestinal manifestations and provide support for targeting tumor necrosis factor in this condition.