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Aim: Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium.Methods and Results: We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly via regulation of ISCs in the crypt niche.Conclusion: We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.

Intestinal epithelial cells (IEC) have important functions in nutrient absorption, barrier integrity, regeneration, pathogen-sensing, and mucus secretion. Goblet cells are a specialized cell type of IEC that secrete Trefoil factor 3 (TFF3) to regulate mucus viscosity and wound healing, but whether TFF3-responsiveness requires a receptor is unclear. Here, we show that leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) is essential for TFF3-mediated functions. LINGO2 immunoprecipitates with TFF3, co-localizes with TFF3 on the cell membrane of IEC, and allows TFF3 to block apoptosis. We further show that TFF3-LINGO2 interactions disrupt EGFR-LINGO2 complexes resulting in enhanced EGFR signaling. Excessive basal EGFR activation in Lingo2 deficient mice increases disease severity during colitis and augments immunity against helminth infection. Conversely, TFF3 deficiency reduces helminth immunity. Thus, TFF3-LINGO2 interactions de-repress inhibitory LINGO2-EGFR complexes, allowing TFF3 to drive wound healing and immunity.

Employing a stochastic model, both Planck and Fokker proposed almost a century ago that stoichiometric chemical reactions proceed by a chain mechanism involving discrete reaction steps. To determine whether such a chain mechanism was in fact a valid mechanism for chemical reactions was the subject of a recent study (Garfinkle, M. 2002. J. Phys. Chem. 106A: 490). Using a thermodynamic-probabilistic algorithm the stochastic reaction paths were found to be in excellent agreement with the observed reaction paths plotted from experimental data. This study was then extended to test the conclusions of Ehrenfest and Prigogine that a chain mechanism dictates that the number of discrete reaction steps required for a chemical reaction to attain equilibrium must be finite. The stochastic and empirical reaction paths were compared using experimental data for first-, second-, and third-order reactions as well as fractional order reactions. The empirical verification was excellent. Key words: chemical thermodynamics, irreversible thermodynamics, reaction kinetics, mass action, natural path. En se basant sur un modele stochastique, Plank et Fokker ont tous les deux propose independamment, il y a pratiquement un siecle, que les reactions chimiques stoechiometriques se produisent par un mecanisme en chaine impliquant des etapes reactionnelles distinctes. Un travail recent (Garfinkle, M. 2002. J. Phys. Chem. 106A: 490) a ete realise pour determiner si un tel mecanisme en chaine est un mecanisme valide pour les reactions chimiques. Sur la base d'un algorithme thermodynamique-probabilistique, on a trouve que les voies reactionnelles stochastiques sont en excellent accord avec les voies reactionnelles observees sur la base de graphiques obtenus a partir de donnees experimentales. Cette etude a alors ete etendue pour verifier la veracite des conclusions de Ehrenfest et Prigogine a l'effet qu'un mecanisme en chaine impose un nombre determine d'etapes reactionnelles distinctes necessaires pour qu'une reaction chimique atteigne un equilibre. On a compare les voies reactionnelles stochastiques et empiriques a l' aide de donnees experimentales pour des reactions d'ordre un, deux et trois ainsi que pour des reactions d'ordres fractionnaires. La verification empirique est excellente. Mots-cles : thermodynamique chimique, thermodynamique irreversible, cinetique reactionnelle, action de masse, voie naturelle. [Traduit par la Redaction], Introduction Classically, the progress of chemical reactions have been described by the empirical rate equations, first elucidated by Guldberg and Waage (see ref. 1) a century and a half ago. [...]

Antigen encounter directs CD4+ T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4+ T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma. Cytokine signaling influences the differentiation of CD4+ T cells into varying functional subsets. Here the authors show that an E3 ubiquitin ligase Cul5 alters TH2 and TH9 development and absence of Cul5 in T cells results in higher levels of allergy-associated IL-4 and IL-9 secreting T cells. [ABSTRACT FROM AUTHOR]

Carl Thompson, ed., Shipwreck in Art and Literature: Images and Interpretations from Antiquity to the Present Day (New York: Routledge, 2014), xii + 269 pp., ISBN 978-0-41564-362-7, $125.00 (hardcover). As […]