Role of interferon-γ and inflammatory monocytes in driving colonic inflammation during acute Clostridium difficile infection in mice.

The inflammatory response to the colonic pathogen Clostridium difficile is characterized by the induction of inflammatory cytokines including Interleukin-23 (IL-23) and interferon-γ (IFN-γ) and the recruitment of myeloid cells including Ly6CHigh monocytes. IL-23 knockout mice showed reduced expression of the monocyte chemokines Ccl4 and Ccl7, but not Ccl2, as well as reduced Ly6CHigh Ly6GMid monocyte recruitment to the colon in response to C. difficile colitis. Clostridium difficile-infected CCR2-/- (CCR2 KO) mice showed a significant defect in Ly6CHigh Ly6GMid monocyte recruitment to the colon in response to C. difficile. Although there was no decrease in expression of the inflammatory cytokines Il1b, Il6 or Tnf or reduction in the severity of colonic histopathology associated with ablation of monocyte recruitment, Slpi and Inos expression was significantly reduced in the colons of these animals. Additionally, neutralization of IFN-γ through the administration of anti-IFN-γ monoclonal antibody resulted in a significant reduction in the expression of the IFN-γ-inducible chemokines Cxcl9 and Cxcl10, but not a reduction in the neutrophil chemokines Cxcl1, Cxcl2 and Ccl3 or the monocyte chemokine Ccl2. Consistently, monocyte and neutrophil recruitment were unchanged following anti-IFN-γ treatment. Additionally, Inos and Slpi expression were unchanged following anti-IFN-γ treatment, suggesting that Inos and Slpi regulation is independent of IFN-γ during C. difficile colitis. Taken together, these data strongly suggest that IL-23 and CCR2 signalling are required for monocyte recruitment during C. difficile colitis. Additionally, these studies also suggest that monocytes, but not IFN-γ, are necessary for full expression of Inos and Slpi in the colon.

Interleukin-22 and CD160 play additive roles in the host mucosal response to Clostridium difficile infection in mice.

Our previous work has shown the significant up-regulation of Il22 and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) as part of the mucosal inflammatory response to Clostridium difficile infection in mice. Others have shown that phosphorylation of STAT3 at mucosal surfaces includes interleukin-22 (IL-22) and CD160-mediated components. The current study sought to determine the potential role(s) of IL-22 and/or CD160 in the mucosal response to C. difficile infection. Clostridium difficile-infected mice treated with anti-IL-22, anti-CD160 or a combination of the two showed significantly reduced STAT3 phosphorylation in comparison to C. difficile-infected mice that had not received either antibody. In addition, C. difficile-infected mice treated with anti-IL-22/CD160 induced a smaller set of genes, and at significantly lower levels than the untreated C. difficile-infected mice. The affected genes included pro-inflammatory chemokines and cytokines, and anti-microbial peptides. Furthermore, histopathological and flow cytometric assessments both showed a significantly reduced influx of neutrophils in C. difficile-infected mice treated with anti-IL-22/CD160. These data demonstrate that IL-22 and CD160 are together responsible for a significant fraction of the colonic STAT3 phosphorylation in C. difficile infection. They also underscore the additive effects of IL-22 and CD160 in mediating both the pro-inflammatory and pro-survival aspects of the host mucosal response in this infection.

Current and Emerging Therapies for Limbal Stem Cell Deficiency.

The corneal epithelium serves to protect the underlying cornea from the external environment and is essential for corneal transparency and optimal visual function. Regeneration of this epithelium is dependent on a population of stem cells residing in the basal layer of the limbus, the junction between the cornea and the sclera. The limbus provides the limbal epithelial stem cells (LESCs) with an optimal microenvironment, the limbal niche, which strictly regulates their proliferation and differentiation. Disturbances to the LESCs and/or their niche can lead to the pathologic condition known as limbal stem cell deficiency (LSCD) whereby the corneal epithelium is not generated effectively. This has deleterious effects on the corneal and visual function, due to impaired healing and secondary corneal opacification. In this concise review, we summarize the characteristics of LESCs and their niche, and present the current and future perspectives in the management of LSCD with an emphasis on restoring the function of the limbal niche.

The association between vision impairment and social participation in community-dwelling adults: a systematic review.

Vision impairment (VI) is an important contributor to the global burden of disability and is associated with decreased well-being. Recent research has attempted to devise a conceptual framework to explain the health consequences of VI. One proposed mechanism by which VI leads to declines in well-being and other adverse health and disability outcomes is through limitations in social participation (SP). SP is an integral component of overall functioning, optimal aging, and well-being, and reductions in SP are associated with lower health-related quality of life. The purpose of this systematic review was to appraise the existing literature on the relationship between VI and SP. The protocol for this review was registered on PROSPERO (CRD42018102767) and adhered to PRISMA guidelines. A comprehensive search of five databases (MEDLINE, EMBASE, PsycINFO, Scopus, Sociology Database) yielded 881 unique studies, of which 19 met inclusion criteria. Among the 19 included studies, 18 concluded that VI was associated with reduced SP and one reported mixed results. Bias was assessed using the Effective Public Health Practice Project Quality Assessment. In the quality assessment, four studies were rated "moderate" and fifteen were rated "weak." There was wide variation in study populations and measurement of VI and SP. In conclusion, there is consensus that VI is associated with reduced SP. However, more rigorous study design and better standardization in the assessment of VI and SP could facilitate valid comparisons across populations, diseases, and levels of VI. Attempts to provide vision rehabilitation and mitigate the effects of VI on overall health and well-being might consider strategies to improve SP.

Longitudinal Associations of Self-reported Vision Impairment With Symptoms of Anxiety and Depression Among Older Adults in the United States.

Importance: Vision impairment (VI) and mental health conditions are highly prevalent among older adults and are major causes of morbidity and health care expenditures. However, there are few nationally representative data from the United States on the longitudinal association between VI and depressive symptoms, and no such data on anxiety symptoms. Objective: To evaluate the longitudinal association and directionality of the association between self-reported VI and clinically significant symptoms of depression and anxiety in older US adults. Design, Setting, and Participants: The National Health and Aging Trends Study, a nationally representative US survey administered annually from 2011 to 2016 to a cohort of Medicare beneficiaries 65 years and older. A total of 7584 participants with complete data on self-reported VI status at baseline were included. Data analysis was performed from February to October 2018. Main Outcomes and Measures: Multivariable Cox proportional hazards regression models were used to evaluate the longitudinal associations between self-reported VI and depression and anxiety symptoms, adjusting for sociodemographics and medical comorbidities and accounting for the complex survey design. Results: There were 7584 participants included in this study. At baseline, the survey-weighted proportion of participants who were women was 56.6%; 53.0% were aged 65 to 74 years, and 8.9% (95% CI, 8.1%-9.8%) had self-reported VI. Symptoms of depression were significantly more common in participants with self-reported VI than those without self-reported VI (31.2%; 95% CI, 27.0%-35.6% vs 12.9%; 95% CI, 11.9%-14.0%; P < .001), as were symptoms of anxiety (27.2%; 95% CI, 23.7%-30.9% vs 11.1%; 95% CI,10.2%-12.0%, P < .001). Baseline self-reported vision status was significantly associated with future report of depression (hazard ratio [HR], 1.33; 95% CI, 1.15-1.55) but not anxiety (HR, 1.06; 95% CI, 0.85-1.31) symptoms. Baseline depression (HR, 1.37; 95% CI, 1.08-1.75) and anxiety (HR, 1.55; 95% CI, 1.19-2.02) symptoms were both significantly associated with future reports of self-reported VI. In a sensitivity analysis excluding data provided by proxy respondents, statistical significance was unchanged and the effect size was similar for all statistical models. Conclusions and Relevance: Older US adults with self-reported VI were more likely to report symptoms of depression in the future, while those who had symptoms of either depression or anxiety were more likely to report VI in the future. This investigation suggests that there is a significant bidirectional and longitudinal association between self-reported VI and mental health symptoms. Furthermore, the study suggests the need for effective strategies to screen for and address depression and anxiety among older US adults with VI.

Role of GM-CSF in the inflammatory cytokine network that regulates neutrophil influx into the colonic mucosa during Clostridium difficile infection in mice.

Clostridium difficile infection in antibiotic-treated mice results in acute colitis characterized by severe intestinal histopathology, robust neutrophil influx, and increased expression of numerous inflammatory cytokines, including GM-CSF. We utilized a neutralizing monoclonal antibody (mAb) against GM-CSF in a murine model to study the role of GM-CSF during acute C. difficile colitis. Cefoperazone-treated mice were challenged with C. difficile (strain 630) spores. Expression of GM-CSF was significantly increased in animals challenged with C. difficile. Treatment with an anti-GM-CSF mAb did not alter C. difficile colonization levels, weight loss, or expression of IL-22 and RegIIIγ. However, expression of the inflammatory cytokines TNFα and IL-1ß, as well as iNOS, was significantly reduced following anti-GM-CSF treatment. Expression of the neutrophil chemokines CXCL1 and CXCL2, but not the chemokines CCL2, CCL4, CXCL9, and CXCL10, was significantly reduced by anti-GM-CSF treatment. Consistent with a decrease in neutrophil-attractant chemokine expression, there were fewer neutrophils in histology sections and a reduction in the expression of secretory leukocyte protease inhibitor (SLPI), a tissue anti-protease that protects against damage by secreted neutrophil elastase. These data indicate that GM-CSF plays a role in the inflammatory signaling network that drives neutrophil recruitment in response to C. difficile infection but does not appear to play a role in clearance of the infection.