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Macrophages are part of the innate immunity and are key players for the maintenance of intestinal homeostasis. They belong to the group of mononuclear phagocytes, which exert bactericidal functions and help to clear apoptotic cells. Moreover, they play essential roles for the maintenance of epithelial integrity and tissue remodeling during wound healing processes and might be implicated in intestinal tumor development. Macrophages are antigen-presenting cells and secrete immune-modulatory factors, like chemokines and cytokines, which are necessary to activate other intestinal immune cells and therefore to shape immune responses in the gut. However, overwhelming activation or increased secretion of pro-inflammatory cytokines might also contribute to the pathogenesis of inflammatory bowel disease. Presently, intestinal macrophages are in the center of intense studies, which might help to develop new therapeutic strategies to counteract the development or treat already existing inflammatory diseases in the gut. In this review, we focus on the origin of intestinal macrophages and, based on current knowledge, discuss their role in the gut during homeostasis and inflammation, as well as during intestinal wound healing and tumor development.

Here we provide compelling evidence that inflammation in a murine model of Crohn’s disease–like inflammation is characterized by an immune reaction presumably directed at a disease-relevant microflora in a genetically susceptible host with impaired mucosal barrier function and bacterial clearance.AbstractCrohn’s disease (CD) patients can be grouped into patients suffering from ileitis, ileocolitis, jejunoileitis, and colitis. The pathophysiological mechanism underlying this regional inflammation is still unknown. Although most murine models of inflammatory bowel disease (IBD) develop inflammation in the colon, there is an unmet need for novel models that recapitulate the spontaneous and fluctuating nature of inflammation as seen in CD. Recently, mice with an intestinal epithelial cell–specific deletion for Caspase-8 (Casp8ΔIEC mice), which are characterized by cell death–driven ileitis and disrupted Paneth cell homeostasis, have been identified as a novel model of CD-like ileitis. Here we uncovered that genetic susceptibility alone is sufficient to drive ileitis in Casp8ΔIEC mice. In sharp contrast, environmental factors, such as a disease-relevant microbial flora, determine colonic inflammation. Accordingly, depending on the microbial environment, isogenic Casp8ΔIEC mice either exclusively developed ileitis or suffered from pathologies in several parts of the gastrointestinal tract. Colitis in these mice was characterized by massive epithelial cell death, leading to spread of commensal gut microbes to the extra-intestinal space and hence an aberrant activation of the systemic immunity. We further uncovered that Casp8ΔIEC mice show qualitative and quantitative changes in the intestinal microbiome associated with an altered mucosal and systemic immune response. In summary, we identified that inflammation in this murine model of CD-like inflammation is characterized by an immune reaction, presumably directed against a disease-relevant microbiota in a genetically susceptible host, with impaired mucosal barrier function and bacterial clearance at the epithelial interface.

A strict cell death control in the intestinal epithelium is indispensable to maintain barrier integrity and homeostasis. In order to achieve a balance between cell proliferation and cell death, a tight regulation of Caspase-8, which is a key player in controlling apoptosis, is required. Caspase-8 activity is regulated by cellular FLIP proteins. These proteins are expressed in different isoforms (cFLIPlong and cFLIPshort) which determine cell death and survival. Interestingly, several viruses encode FLIP proteins, homologous to cFLIPshort, which are described to regulate Caspase-8 and the host cell death machinery. In the current study a mouse model was generated to show the impact of viral FLIP (vFLIP) from Kaposi's Sarcoma-associated Herpesvirus (KSHV)/ Human Herpesvirus-8 (HHV-8) on cell death regulation in the gut. Our results demonstrate that expression of vFlip in intestinal epithelial cells suppressed cFlip expression, but protected mice from lethality, tissue damage and excessive apoptotic cell death induced by genetic cFlip deletion. Finally, our model shows that vFlip expression decreases cFlip mediated Caspase-8 activation in intestinal epithelial cells. In conclusion, our data suggests that viral FLIP neutralizes and compensates for cellular FLIP, efficiently counteracting host cell death induction and facilitating further propagation in the host organism.

The intestinal epithelium constitutes an indispensable single-layered barrier to protect the body from invading pathogens, antigens or toxins. At the same time, beneficial nutrients and water have to be absorbed by the epithelium. To prevent development of intestinal inflammation or tumour formation, intestinal homeostasis has to be tightly controlled and therefore a strict balance between cell death and proliferation has to be maintained. The proinflammatory cytokine tumour necrosis factor alpha (TNFα) was shown to play a striking role for the regulation of this balance in the gut. Depending on the cellular conditions, on the one hand TNFα is able to mediate cell survival by activating NFκB signalling. On the other hand, TNFα might trigger cell death, in particular caspase-dependent apoptosis but also caspase-independent programmed necrosis. By regulating these cell death and survival mechanisms, TNFα exerts a variety of beneficial functions in the intestine. However, TNFα signalling is also supposed to play a critical role for the pathogenesis of inflammatory bowel disease (IBD), infectious diseases, intestinal wound healing and tumour formation. Here we review the literature about the physiological and pathophysiological role of TNFα signalling for the maintenance of intestinal homeostasis and the benefits and difficulties of anti-TNFα treatment during IBD.

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn’s disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD. Dietary lipids are linked to the development of inflammatory bowel diseases through unclear mechanisms. Here, the authors report that dietary polyunsaturated fatty acids trigger intestinal inflammation resembling aspects of Crohn’s disease, which is restricted by glutathione peroxidase 4 in the intestinal epithelium.

Inflammatory bowel diseases present with elevated levels of intestinal epithelial cell (IEC) death, which compromises the gut barrier, activating immune cells and triggering more IEC death. The endogenous signals that prevent IEC death and break this vicious cycle, allowing resolution of intestinal inflammation, remain largely unknown. Here we show that prostaglandin E2 signalling via the E-type prostanoid receptor 4 (EP4) on IECs represses epithelial necroptosis and induces resolution of colitis. We found that EP4 expression correlates with an improved IBD outcome and that EP4 activation induces a transcriptional signature consistent with resolution of intestinal inflammation. We further show that dysregulated necroptosis prevents resolution, and EP4 agonism suppresses necroptosis in human and mouse IECs. Mechanistically, EP4 signalling on IECs converges on receptor-interacting protein kinase 1 to suppress tumour necrosis factor-induced activation and membrane translocation of the necroptosis effector mixed-lineage kinase domain-like pseudokinase. In summary, our study indicates that EP4 promotes the resolution of colitis by suppressing IEC necroptosis. Patankar et al. identify E-type prostanoid receptor 4 as a negative regulator of tumour necrosis factor signalling and mixed-lineage kinase domain-like pseudokinase activation, thereby suppressing necroptosis of intestinal epithelial cells and promoting resolution of intestinal inflammation.

Although induction of host cell death is a pivotal step during bacteria-induced gastroenteritis, the molecular regulation remains to be fully characterized. To expand our knowledge, we investigated the role of the central cell death regulator Caspase-8 in response to Salmonella Typhimurium. Here, we uncovered that intestinal salmonellosis was associated with strong upregulation of members of the host cell death machinery in intestinal epithelial cells (IECs) as an early event, suggesting that elimination of infected IECs represents a host defense strategy. Indeed, Casp8∆IEC mice displayed severe tissue damage and high lethality after infection. Additional deletion of Ripk3 or Mlkl rescued epithelial cell death and lethality of Casp8∆IEC mice, demonstrating the crucial role of Caspase-8 as a negative regulator of necroptosis. While Casp8∆IECTnfr1−/− mice showed improved survival after infection, tissue destruction was similar to Casp8∆IEC mice, indicating that necroptosis partially depends on TNF-α signaling. Although there was no impairment in antimicrobial peptide secretion during the early phase of infection, functional Caspase-8 seems to be required to control pathogen colonization. Collectively, these results demonstrate that Caspase-8 is essential to prevent Salmonella Typhimurium induced enteritis and to ensure host survival by two different mechanisms: maintenance of intestinal barrier function and restriction of pathogen colonization.