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Lars Eckmann

Publications and source records attributed to Lars Eckmann.

At least 19 recordsLinked to original sources
PubMed2025

Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene.

BACKGROUND & AIMS: Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake. METHODS: Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus. RESULTS: We report that the autoimmune PTPN2 loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib. CONCLUSION: Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

Humans↗
PubMed2006

Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells.

The mechanisms by which commensal bacteria suppress inflammatory signalling in the gut are still unclear. Here, we present a cellular mechanism whereby the polarity of intestinal epithelial cells (IECs) has a major role in colonic homeostasis. TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-kappaB activation and cDNA microarray analysis. Whereas basolateral TLR9 signals IkappaBalpha degradation and activation of the NF-kappaB pathway, apical TLR9 stimulation invokes a unique response in which ubiquitinated IkappaB accumulates in the cytoplasm preventing NF-kappaB activation. Furthermore, apical TLR9 stimulation confers intracellular tolerance to subsequent TLR challenges. IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-kappaB activation threshold and these mice are highly susceptible to experimental colitis. Our data provide a case for organ-specific innate immunity in which TLR expression in polarized IECs has uniquely evolved to maintain colonic homeostasis and regulate tolerance and inflammation.

Animals↗
PubMed2006

Polymeric immunoglobulin receptor in intestinal immune defense against the lumen-dwelling protozoan parasite Giardia.

The polymeric Ig receptor (pIgR) is conserved in mammals and has an avian homologue, suggesting evolutionarily important functions in vertebrates. It transports multimeric IgA and IgM across polarized epithelia and is highly expressed in the intestine, yet little direct evidence exists for its importance in defense against common enteric pathogens. In this study, we demonstrate that pIgR can play a critical role in intestinal defense against the lumen-dwelling protozoan parasite Giardia, a leading cause of diarrheal disease. The receptor was essential for the eradication of Giardia when high luminal IgA levels were required. Clearance of Giardia muris, in which IgA plays a dominant role, was severely compromised in pIgR-deficient mice despite significant fecal IgA output at 10% of normal levels. In contrast, eradication of the human strain Giardia lamblia GS/M, for which adaptive immunity is less IgA dependent in mice, was unaffected by pIgR deficiency, indicating that pIgR had no physiologic role when lower luminal IgA levels were sufficient for parasite elimination. Immune IgA was greatly increased in the serum of pIgR-deficient mice, conferred passive protection against Giardia, and recognized several conserved giardial Ags, including ornithine carbamoyltransferase, arginine deiminase, alpha-enolase, and alpha- and beta-giardins, that are also detected in human giardiasis. Corroborative observations were made in mice lacking the J chain, which is required for pIgR-dependent transepithelial IgA transport. These results, together with prior data on pIgR-mediated immune neutralization of luminal cholera toxin, suggest that pIgR is essential in intestinal defense against pathogenic microbes with high-level and persistent luminal presence.

Animals↗
PubMed2006

Epithelial cell I kappa B-kinase beta has an important protective role in Clostridium difficile toxin A-induced mucosal injury.

Toxin A released by Clostridium difficile interacts with the single layer of intestinal epithelial cells that lines the host's intestinal tract and leads to mucosal damage and inflammation that manifests clinically as antibiotic-associated diarrhea and pseudomembranous colitis. Activation of the transcription factor NF-kappaB in intestinal epithelial cells is important for regulating the expression of epithelial cell proinflammatory genes and cell survival. However, the role of NF-kappaB activation in the pathogenesis of C. difficile toxin A-induced colitis is unknown. To determine the functional importance in vivo of NF-kappaB activation in intestinal epithelium in the pathogenesis of C. difficile-induced colitis, we used mutant mice that do not activate the classical NF-kappaB signaling pathway in intestinal epithelial cells due to a conditional deficiency in those cells of the IkappaB-kinase beta (IKKbeta) subunit of IKK. C. difficile toxin A challenge of intestinal loops in intestinal epithelial cell IKKbeta-deficient mice induced a rapid and significant increase in intestinal epithelial apoptosis compared with littermate controls. This was accompanied by a significant increase in acute mucosal inflammation, mucosal injury, luminal fluid secretion, and bacterial translocation. We conclude that activation of intestinal epithelial cell NF-kappaB by toxin A plays an important host mucosal protective role after C. difficile toxin A exposure that is mediated, at least in part, through promoting epithelial cell survival by abrogating epithelial cell apoptosis.

Animals↗
PubMed2006

Sensor molecules in intestinal innate immunity against bacterial infections.

PURPOSE OF REVIEW: Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-containing proteins are innate immune sensors for microbial signature molecules. This review highlights new insights into the functions of these sensors in intestinal physiology. RECENT FINDINGS: TLRs are membrane bound and survey the extracellular space for microbe-derived molecules, while NOD-containing proteins are cytoplasmic and detect microbial molecules in the cytoplasm. Most microbial sensors recognize components of the bacterial cell wall and its appendages. For example, TLR4 detects lipopolysaccharide in the Gram-negative bacterial cell wall. TLR5 recognizes flagellin, a component of bacterial flagella required for motility. NOD1 recognizes diaminopimelic acid-containing dipeptide or tripeptide motifs in the Gram-positive bacterial cell wall, while NOD2 detects muramyl dipeptide, a ubiquitous cell wall peptidoglycan motif. These sensors are important for host defense against gastrointestinal pathogens. Thus, TLR4 is required for Salmonella eradication, NOD1 contributes to controlling Helicobacter pylori infection, and NOD2 is involved in mucosal defense against Listeria monocytogenes. These sensors also regulate mucosal inflammation independent of pathogen infections. SUMMARY: Toll-like receptors and nucleotide-binding oligomerization domain-containing proteins not only play critical roles in host defense against known gastrointestinal bacterial pathogens, but also contribute to mucosal homeostasis in the apparent absence of such pathogens.

Animals↗
PubMed2006

Animal models of inflammatory bowel disease: lessons from enteric infections.

Mouse models of intestinal inflammation have played a key role in understanding the mechanisms that govern the inflammatory response in the intestine, and in designing new therapeutic strategies in the treatment of patients with inflammatory bowel disease (IBD). Most of these models use chemical challenges, whereas relatively few robust models of intestinal inflammation caused by microbial infection are known. Two common models of infectious murine colitis and typhlitis are infection with the murine epithelial-adherent pathogen, Citrobacter rodentium, and infection of streptomycin-pretreated mice with Salmonella typhimurium. Studies in these models have helped to define the interactions between bacterial pathogens and host immune defenses, thus broadening the understanding of host-microbial interactions in the intestinal tract. Furthermore, such models help to determine the physiologic consequences of neutralizing specific mediators and signaling pathways implicated in inflammation on antimicrobial host defense.

Animals↗
PubMed2005

Tumor promotion by caspase-resistant retinoblastoma protein.

The retinoblastoma (RB) protein regulates cell proliferation and cell death. RB is cleaved by caspase during apoptosis. A mutation of the caspase-cleavage site in the RB C terminus has been made in the mouse Rb-1 locus; the resulting Rb-MI mice are resistant to endotoxin-induced apoptosis in the intestine. The Rb-MI mice do not exhibit increased tumor incidence, because the MI mutation does not disrupt the Rb tumor suppressor function. In this study, we show that Rb-MI can promote the formation of colonic adenomas in the p53-null genetic background. Consistent with this tumor phenotype, Rb-MI reduces colorectal epithelial apoptosis and ulceration caused by dextran sulfate sodium. By contrast, Rb-MI does not affect the lymphoma phenotype of p53-null mice, in keeping with its inability to protect thymocytes and splenocytes from apoptosis. The Rb-MI protein is expressed and phosphorylated in the tumors, thereby inactivating its growth suppression function. These results suggest that RB tumor suppressor function, i.e., inhibition of proliferation, is inactivated by phosphorylation, whereas RB tumor promoting function, i.e., inhibition of apoptosis, is inactivated by caspase cleavage.

Animals↗
PubMed2005

Intestinal mucosal responses to microbial infection.

Infections of the human intestinal tract with foodborne and waterborne pathogens are among the leading causes of morbidity and death in the world. Upon ingestion, such pathogens commonly pass through the stomach in sufficient numbers to establish infection in the small intestine or colon. The subsequent interactions with the host depend critically on the particular pathogen, ranging from mere presence in the intestinal lumen and minimal interaction with the epithelium to highly mucosal invasive with rapid systemic spread. This article addresses the morphological and molecular changes that occur in the intestinal mucosa after infection with a selected yet representative spectrum of enteric pathogens, ranging from luminally restricted but epithelial adherent, epithelial invasive, to mucosally invasive, with a focus on intestinal epithelial responses.

Animals↗
PubMed2005

Cathelicidin mediates innate intestinal defense against colonization with epithelial adherent bacterial pathogens.

Cathelicidin-related antimicrobial peptide (mCRAMP), the sole murine cathelicidin, is encoded by the gene Cnlp. We show that mCRAMP expression in the intestinal tract is largely restricted to surface epithelial cells in the colon. Synthetic mCRAMP had antimicrobial activity against the murine enteric pathogen Citrobacter rodentium, which like the related clinically important human pathogens enteropathogenic Escherichia coli and enterohemorrhagic E. coli, adheres to the apical membrane of intestinal epithelial cells. Colon epithelial cell extracts from Cnlp+/+ mice had significantly greater antimicrobial activity against C. rodentium than those of mutant Cnlp-/- mice that lack mCRAMP. Cnlp-/- mice developed significantly greater colon surface and crypt epithelial cell colonization, surface epithelial cell damage, and systemic dissemination of infection than Cnlp+/+ mice after oral infection with C. rodentium. Moreover, Cnlp+/+ mice were protected from oral infections with C. rodentium inocula that infected the majority of Cnlp-/- mice. These results establish cathelicidin as an important component of innate antimicrobial defense in the colon.

Animals↗
PubMed2005

Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing.

Variants of NOD2, an intracellular sensor of bacteria-derived muramyl dipeptide (MDP), increase susceptibility to Crohn's disease (CD). These variants are thought to be defective in activation of nuclear factor kappaB (NF-kappaB) and antibacterial defenses, but CD clinical specimens display elevated NF-kappaB activity. To illuminate the pathophysiological function of NOD2, we introduced such a variant to the mouse Nod2 locus. Mutant mice exhibited elevated NF-kappaB activation in response to MDP and more efficient processing and secretion of the cytokine interleukin-1beta (IL-1beta). These effects are linked to increased susceptibility to bacterial-induced intestinal inflammation and identify NOD2 as a positive regulator of NF-kappaB activation and IL-1beta secretion.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2005

NOD2 and Crohn's disease: loss or gain of function?

The human nucleotide binding and oligomerization domain (NOD)-containing protein family consists of some 25 members related to the Apaf-1/Ced-4 family of apoptosis regulators and certain plant disease-resistance genes (Inohara et al., 2004). One member, NOD2 (CARD15), has gained recent prominence through its association with increased susceptibility to several clinically important human inflammatory diseases, especially Crohn's disease (CD). NOD2 is a cytoplasmic molecule involved in sensing microbial cell wall components and regulating inflammatory processes and apoptosis. This review focuses on recent insights into the functions of normal and variant NOD2 proteins and the pathogenetic mechanisms underlying NOD2-associated inflammatory diseases.

Animals↗
PubMed2005

Defence molecules in intestinal innate immunity against bacterial infections.

PURPOSE OF REVIEW: Antimicrobial proteins are key effector molecules of innate immunity. The review discusses recent progress in understanding the function of these host defence molecules in intestinal physiology. RECENT FINDINGS: All antimicrobial proteins can inhibit or kill bacteria in vitro, but differ markedly in their localization, regulation, and additional activities. alpha-Defensins are expressed constitutively in human neutrophils and small intestinal Paneth cells, where they require proteolytic processing and signal-induced release to be active in the intestinal lumen. Neutrophil-derived alpha-defensins can inhibit angiogenesis. Cryptdin-related sequence peptides form a subfamily of alpha-defensins in murine but not human Paneth cells that can form covalently linked heterodimers, leading to increased structural diversity and antimicrobial target range. Human beta-defensins (hBD) are expressed prominently in epithelial cells of the intestinal tract and other organs exposed to the environment. Their epithelial production is either constitutive, as exemplified by hBD-1, or strongly inducible, as shown for hBD-2,-3, and -4. Human cathelicidin, LL-37/hCAP18, is expressed constitutively by differentiated epithelial cells in the colon and stomach, but not the small intestine, as well as neutrophils and mast cells. It has multiple functions beyond its antimicrobial activity, including promotion of angiogenesis, attraction of leukocyte subsets, and activation of chemokine secretion. Angiogenins are a family of host defence-related ribonucleases, of which at least one is secreted by murine Paneth cells. SUMMARY: The differential expression of diverse antimicrobial proteins in the gastrointestinal tract suggests that they occupy distinct functional niches in mucosal innate defence, which holds promise for pharmacological exploitation of their antimicrobial properties.

Animals↗
PubMed2005

Toll-like receptor 9-induced type I IFN protects mice from experimental colitis.

Experimental colitis is mediated by inflammatory or dysregulated immune responses to microbial factors of the gastrointestinal tract. In this study we observed that administration of Toll-like receptor 9 (TLR9) agonists suppressed the severity of experimental colitis in RAG1-/- but not in SCID mice. This differential responsiveness between phenotypically similar but genetically distinct animals was related to a partial blockade in TLR9 signaling and defective production of type I IFN (i.e., IFN-alpha/beta) in SCID mice upon TLR9 stimulation. The addition of neutralization antibodies against type I IFN abolished the antiinflammatory effects induced by TLR9 agonists, whereas the administration of recombinant IFN-beta mimicked the antiinflammatory effects induced by TLR9 agonists in this model. Furthermore, mice deficient in the IFN-alpha/beta receptor exhibited more severe colitis than wild-type mice did upon induction of experimental colitis. These results indicate that TLR9-triggered type I IFN has antiinflammatory functions in colitis. They also underscore the important protective role of type I IFN in intestinal homeostasis and suggest that strategies to modulate innate immunity may be of therapeutic value for the treatment of intestinal inflammatory conditions.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Chemokine receptor CCR6 transduces signals that activate p130Cas and alter cAMP-stimulated ion transport in human intestinal epithelial cells.

Human colon epithelial cells express the G protein-coupled receptor CCR6, the sole receptor for the chemokine CCL20 (also termed MIP-3alpha). CCL20 produced by intestinal epithelial cells is upregulated in response to proinflammatory stimuli and microbial infection, and it chemoattracts leukocytes, including CCR6-expressing immature myeloid dendritic cells, into sites of inflammation. The aim of this study was to determine whether CCR6 expressed by intestinal epithelial cells acts as a functional receptor for CCL20 and whether stimulation with CCL20 alters intestinal epithelial cell functions. The human colon epithelial cell lines T84, Caco-2, HT-29, and HCA-7 were used to model colonic epithelium. Polarized intestinal epithelial cells constitutively expressed CCR6, predominantly on the apical side. Consistent with this, apical stimulation of polarized intestinal epithelial cells resulted in tyrosine phosphorylation of the p130 Crk-associated substrate (Cas), an adaptor/scaffolding protein that localizes in focal adhesions and has a role in regulating cytoskeletal elements important for cell attachment and migration. In addition, CCL20 stimulation inhibited agonist-stimulated production of the second messenger cAMP and cAMP-mediated chloride secretory responses by intestinal epithelial cells. Inhibition was abrogated by pertussis toxin, consistent with signaling through Galphai proteins that negatively regulate adenylyl cyclases and cAMP production. These data indicate that signaling events, occurring via the activation of the apically expressed chemokine receptor CCR6 on polarized intestinal epithelial cells, alter specialized intestinal epithelial cell functions, including electrogenic ion secretion and possibly epithelial cell adhesion and migration.

Blotting, Western↗
PubMed2004

An important role for polymeric Ig receptor-mediated transport of IgA in protection against Streptococcus pneumoniae nasopharyngeal carriage.

The importance of IgA for protection at mucosal surfaces remains unclear, and in fact, it has been reported that IgA-deficient mice have fully functional vaccine-induced immunity against several bacterial and viral pathogens. The role of respiratory Ab in preventing colonization by Streptococcus pneumoniae has now been examined using polymeric IgR knockout (pIgR(-/-)) mice, which lack the ability to actively secrete IgA into the mucosal lumen. Intranasal vaccination with a protein conjugate vaccine elicited serotype-specific anti-capsular polysaccharide Ab locally and systemically, and pIgR(-/-) mice produced levels of total serum Ab after vaccination that were similar to wild-type mice. However, pIgR(-/-) mice had approximately 5-fold more systemic IgA and 6-fold less nasal IgA Ab than wild-type mice due to defective transport into mucosal tissues. Wild-type, but not pIgR(-/-) mice were protected against infection with serotype 14 S. pneumoniae, which causes mucosal colonization but does not induce systemic inflammatory responses in mice. The relative importance of secretory IgA in host defense was further shown by the finding that intranasally vaccinated IgA gene-deficient mice were not protected from colonization. Although secretory IgA was found to be important for protection against nasal carriage, it does not appear to have a crucial role in immunity to systemic pneumococcus infection, because both vaccinated wild-type and pIgR(-/-) mice were fully protected from lethal systemic infection by serotype 3 pneumococci. The results demonstrate the critical role of secretory IgA in protection against pneumococcal nasal colonization and suggest that directed targeting to mucosal tissues will be needed for effective vaccination in humans.

Administration, Intranasal↗
PubMed2004

IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.

A link between inflammation and cancer has long been suspected, but its molecular nature remained ill defined. A key player in inflammation is transcription factor NF-kappaB whose activity is triggered in response to infectious agents and proinflammatory cytokines via the IkappaB kinase (IKK) complex. Using a colitis-associated cancer model, we show that although deletion of IKKbeta in intestinal epithelial cells does not decrease inflammation, it leads to a dramatic decrease in tumor incidence without affecting tumor size. This is linked to increased epithelial apoptosis during tumor promotion. Deleting IKKbeta in myeloid cells, however, results in a significant decrease in tumor size. This deletion diminishes expression of proinflammatory cytokines that may serve as tumor growth factors, without affecting apoptosis. Thus, specific inactivation of the IKK/NF-kappaB pathway in two different cell types can attenuate formation of inflammation-associated tumors. In addition to suppressing apoptosis in advanced tumors, IKKbeta may link inflammation to cancer.

Animals↗