Defects in Actin Dynamics Lead to an Autoinflammatory Condition through the Upregulation of CXCL5

Destrin (DSTN) is a member of the ADF/cofilin family of proteins and is an important regulator of actin dynamics. The primary function of destrin is to depolymerize filamentous actin into its monomeric form and promote filament severing. While progress has been made in understanding the biochemical functions of the ADF/cofilin proteins, the study of an animal model for cells deficient for DSTN provides an opportunity to investigate the physiological processes regulated by proper actin dynamics in vivo. A spontaneous mouse mutant, corneal disease 1(corn1), is deficient for DSTN, which causes epithelial hyperproliferation and neovascularization in the cornea. Dstn(corn1) mice exhibit an actin dynamics defect in the cornea as evidenced by the formation of actin stress fibers in the epithelial cells. Previously, we observed a significant infiltration of leukocytes into the cornea of Dstn(corn1) mice as well as the upregulation of proinflammatory molecules. In this study, we sought to characterize this inflammatory condition and explore the physiological mechanism through which a loss of Dstn function leads to inflammation.Through immunofluorescent analyses, we observed a significant recruitment of neutrophils and macrophages to the Dstn(corn1) cornea, demonstrating that the innate immune system is spontaneously activated in this mutant. The inflammatory chemokine, CXCL5, was ectopically expressed in the corneal epithelial cells of Dstn(corn1) mice, and targeting of the receptor for this chemokine inhibited neutrophil recruitment. An inflammatory reaction was not observed in the cornea of allelic mutant strain, Dstn(corn1-2J), which has a milder defect in actin dynamics in the corneal epithelial cells.This study shows that severe defects in actin dynamics lead to an autoinflammatory condition that is mediated by the expression of CXC chemokines

Somatic Dnmt3a inactivation leads to slow, canonical DNA methylation loss in murine hematopoietic cells

Mutations in the gene encoding DNA methyltransferase 3A

Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: results from a national, multicenter survey

Background: There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. Methods: The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group - KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients' outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. Results: One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p < 0.0001). SARS-CoV-2 assay more often resulted positive in KCG than in KDG (75,5% vs 20%; p < 0.0001). Short-term follow data showed minor complications. Comparing KDG with a KD-Historical Italian cohort (598 patients), no statistical difference was found in terms of clinical manifestations and laboratory data. Conclusion: Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths

Assessment of granulocyte and monocyte ratios in the peripheral leukocyte population of A.BY WT and <i>Dstn^corn1</i> mice.

<p>A flow cytometric analysis revealed that the ratios of granulocytes, which are comprised mostly of neutrophils, and monocytes, which are the precursor to macrophages, are not significantly different between A.BY WT and <i>Dstn^corn1</i> mice. Ratios are expressed as the percentage of cells compared to the total leukocyte number. Error bars represent SEM.</p

Inflammatory cell recruitment in the corneas of <i>Dstn</i> mutant mice.

<p>(A): Immunofluorescent staining for macrophages (F4/80, red) and neutrophils (myeloperoxidase, green) in WT, <i>Dstn^corn1</i>, and <i>Dstn^corn1-2J</i> cornea at P14. Neutrophils are recruited to the stromal area in <i>Dstn^corn1</i>, but not WT or <i>Dstn^corn1-2J</i> cornea. Sections are counterstained with DAPI (blue). The central region of the cornea is shown in all images. The scale bar corresponds to 10 µm. (B): Quantification of inflammatory cells in WT and <i>Dstn^corn1</i> mice. Accumulation of neutrophils is observed in <i>Dstn^corn1</i> cornea as compared to WT beginning at P14. Significantly higher numbers of macrophages are also present in <i>Dstn^corn1</i> cornea beginning at P14, and most significantly at P28. Error bars represent standard error of measurement (SEM). * denotes statistical significance by <i>t</i>-test. (C): Quantification of inflammatory cells in different regions of the cornea shows that the greatest numbers of neutrophils and macrophages accumulate in the peripheral region, the area adjacent to the limbal vasculature. Error bars represent SEM. * denotes statistical significance by <i>t</i>-test.</p