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Infectious and inflammatory diseases in the intestine remain a serious threat for patients world-wide. Reprogramming of the intestinal epithelium towards a protective effector state is important to manage inflammation and immunity and can be therapeutically targeted. The role of epigenetic regulatory enzymes within these processes is not yet defined. Here, we use a mouse model that has an intestinal-epithelial specific deletion of the histone demethylase Lsd1 (cKO mice), which maintains the epithelium in a fixed reparative state. Challenge of cKO mice with bacteria-induced colitis or a helminth infection model both resulted in increased pathogenesis. Mechanistically, we discovered that LSD1 is important for goblet cell maturation and goblet-cell effector molecules such as RELMß. We propose that this may be in part mediated by directly controlling genes that facilitate cytoskeletal organization, which is important in goblet cell biology. This study therefore identifies intestinal-epithelial epigenetic regulation by LSD1 as a critical element in host protection from infection., Author summary The epithelium that lines our intestine has the important task of taking up nutrients, while also providing a barrier against pathogens. The intestinal epithelium performs these different tasks by having specialized cell types; enterocytes take up nutrients whereas goblet cells are in charge of producing a mucus layer. In addition, goblet cells can be stimulated to make special antimicrobial proteins. This occurs in response to cues called cytokines that come from immune cells, which are able to detect and act on the presence of pathogens such as bacteria or parasitic worms. In this study, we found that LSD1, an enzyme that controls gene expression, was important for goblet cells. Mice that lacked LSD1 specifically in their intestinal epithelium were unable to respond to cytokines and could not defend themselves against bacterial and parasitic infections. In part, we also made use of a specific inhibitor against the enzyme activity of LSD1. This inhibitor also blocked goblet cell differentiation and goblet-cell specific antimicrobial responses to cytokines. We are thus able to manipulate epithelial responses, which may be an important tool in the future to treat patients with infectious diseases.

Infectious and inflammatory diseases in the intestine remain a serious threat for patients world-wide. Reprogramming of the intestinal epithelium towards a protective effector state is important to manage inflammation and immunity. The role of epigenetic regulatory enzymes within these processes is not yet defined. Here, we use a mouse model that has an intestinal-epithelial specific deletion of the histone demethylaseLsd1(cKO mice), which maintains the epithelium in a fixed reparative state. Challenge of cKO mice with chemical-induced colitis, bacteria-induced colitis, and a helminth infection model all resulted in increased pathogenesis. Mechanistically, we discovered that LSD1 directly controls genes that facilitate cytoskeletal organization, and that this is relevant for epithelial attachment as well as for goblet-cell specific effector responses.This study therefore identifies intestinal-epithelial epigenetic regulation by LSD1 as a critical element in host protection from inflammation and infection.

SUMMARYSmooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle may have. Here, we show that smooth muscle is the dominant supplier of BMP antagonists, which are niche factors that are essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors can render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we provide evidence that MMP17 affects intestinal epithelial reprogramming indirectly by cleaving the matricellular protein PERIOSTIN, which itself is able to activate YAP. Together, we identify an important signaling axis that firmly establishes a role for smooth muscle as a modulator of intestinal epithelial regeneration and the intestinal stem cell niche.

How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.

et al., Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease., This work was funded by the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad; SAF2012-34296 to J.M.R. and SAF2013-45258-P to M.R.C.), the Fundación La Marató TV3 (264/C/2012 to J.M.R.), the Spanish Ministry of Health (Ministerio de Sanidad y Consumo) Red de Investigación Cardiovascular (RIC) cofounded by FEDER (grants RD06/0042/0022 to J.M.R. and RD12/0042/0023 to A.G.A), and the Spanish Council for Scientific Research (CSIC; to M.R.C.). The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness and the Pro-CNIC Foundation. J.O. is the holder of an FPI fellowship from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad; BES 2010-034552). The cost of this publication has been paid in part by FEDER funds.

Matrix metalloproteinases are involved in vascular remodeling. Little is known about their immune regulatory role in atherosclerosis. Here we show that mice deficient for MT4-MMP have increased adherence of macrophages to inflamed peritonea, and larger lipid deposits and macrophage burden in atherosclerotic plaques. We also demonstrate that MT4-MMP deficiency results in higher numbers of patrolling monocytes crawling and adhered to inflamed endothelia, and the accumulation of Mafb+ apoptosis inhibitor of macrophage (AIM)+ macrophages at incipient atherosclerotic lesions in mice. Functionally, MT4-MMP-null Mafb+AIM+ peritoneal macrophages express higher AIM and scavenger receptor CD36, are more resistant to apoptosis, and bind acLDL avidly, all of which contribute to atherosclerosis. CCR5 inhibition alleviates these effects by hindering the enhanced recruitment of MT4-MMP-null patrolling monocytes to early atherosclerotic lesions, thus blocking Mafb+AIM+ macrophage accumulation and atherosclerosis acceleration. Our results suggest that MT4-MMP targeting may constitute a novel strategy to boost patrolling monocyte activity in early inflammation., This study was supported by grants from the Spanish Ministry of Economy, Industry and Competitiveness (MEIC; RD12/0042/0023 [FEDER cofunded] and SAF2014-52050R and SAF2017-83229R to A.G.A., SAF2015-64287R and SAF2015-71878-REDT to M.R., RD12/0042/0053 [FEDER cofunded] and SAF2015-64767-R to J.M-G., and SAF2016-79490-R and RD12/0042/0028 [FEDER cofunded] to V.A.) and from La Marató TV3 Foundation. C.C., M.M-A., and L.A-H. were funded by fellowships from the Spanish Ministry of Education, MEIC, and La Caixa-CNIC, respectively. C.R. was funded by a competitive postdoctoral contract grant FPDI-2013-17423 from MEIC. The CNIC is supported by the Spanish MEIC and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MEIC award SEV-2015-0505).

Cadherin-based intercellular adhesions are essential players in epithelial homeostasis, but their dynamic regulation during tissue morphogenesis and remodeling remain largely undefined. Herein, we characterize an unexpected role for the membrane-anchored metalloproteinase MT2-MMP in regulating epithelial cell quiescence. Following coimmunoprecipitation and mass spectrometry, the MT2-MMP cytosolic tail was found to interact with the zonula occludens protein-1 (ZO-1) at the apical junctions of polarized epithelial cells. Functionally, MT2-MMP localizes in the apical domain of epithelial cells where it cleaves E-cadherin and promotes epithelial cell accumulation, a phenotype observed in 2D polarized cells as well as 3D cysts. MT2-MMP-mediated cleavage subsequently disrupts apical E-cadherin-mediated cell quiescence resulting in; i) relaxed apical cortical tension favoring cell extrusion and ii) re-sorting of Src kinase activity to junctional complexes, thereby promoting proliferation. Physiologically, MT2-MMP lossof- function alters E-cadherin distribution leading to impaired 3D organoid formation by mouse colonic epithelial cells ex vivo and reduction of cell proliferation within intestinal crypts in vivo. Taken together, these studies identify an MT2-MMP/E-cadherin axis that functions as a novel regulator of epithelial cell homeostasis in vivo. © 2017. Published by The Company of Biologists Ltd. Locked until 13.10.2018 due to copyright restrictions.

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/early/2015/05/11/CIRCRESAHA.117.305108, RATIONALE: Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries. These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome. OBJECTIVE: To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology. METHODS AND RESULTS: Screening of patients with inherited thoracic aortic aneurysms and dissections identified a missense mutation (R373H) in the MMP17 gene that prevented the expression of the protease in human transfected cells. Using a loss-of-function genetic mouse model, we demonstrated that the lack of Mmp17 resulted in the presence of dysfunctional vascular smooth muscle cells and altered extracellular matrix in the vessel wall; and it led to increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. We also showed that Mmp17-mediated osteopontin cleavage regulated vascular smooth muscle cell maturation via c-Jun N-terminal kinase signaling during aorta wall development. Some features of the arterial phenotype were prevented by re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment in Mmp17-null neonates. CONCLUSIONS: Mmp17 proteolytic activity regulates vascular smooth muscle cell phenotype in the arterial vessel wall, and its absence predisposes to thoracic aortic aneurysm in mice. The rescue of part of the vessel-wall phenotype by a lentiviral strategy opens avenues for therapeutic intervention in these life-threatening disorders, This work was supported by grants from the Ministerio de Economía y Competitividad (RD12/0042/0022 to JMR, RD12/0042/0024 to MS, and RD12/0042/0023 to AGA [FEDER cofounded], and SAF2011-25619 to AGA). MM-A was funded by a MINECO fellowship. SILAC analysis was performed in the Proteomics Laboratory at Vall d'Hebron Institute of Oncology (VHIO), a member of ProteoRed, PRB2-ISCIII, supported by grant PT13/0001. The CNIC is supported by the Ministerio de Economía y Competitividad and the Pro- CNIC Foundation

The response to environmental cues such as inflammatory stimuli requires coordinated cellular functions. Certain proteins have functions on both sides of the plasma membrane to allow coordination between the extracellular and intracellular milieus. The membrane-anchored matrix metalloproteinase MT1-MMP is well positioned to sense and modify the extracellular environment by processing matrix components, transmembrane proteins and soluble factors. Recent findings show, however, that MT1-MMP also plays unexpected intracellular roles in macrophages through its location at the plasma membrane, the Golgi or the nucleus, impacting cell motility, metabolism and gene transcription. MT1-MMP is thus an example of the evolutionary diversification of protein function, allowing optimal coordination between extracellular stimuli and cellular responses. It remains to be determined whether these new MT1-MMP functions are specific to macrophages, professional phagocytes involved in inflammation, or are present in other inflammation-responsive cells. In this review, we will summarize these site-specific MT1-MMP functions in macrophages and comment on the possible conservation of these functions in endothelial cells.