Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration

Neutrophil [polymorphonuclear leukocyte (PMN)] transepithelial migration (TEM) is a hallmark of inflammatory mucosal disorders. PMN TEM is associated with epithelial injury; however, mechanisms involved in this process are not well defined. The current work describes a new mechanism whereby deposition of PMN membranederived microparticles (PMNâ MPs) onto intestinal epithelial cells (IECs) during TEM leads to loss of epithelial cadherins, thus promoting epithelial injury and increased PMN recruitment. PMNâ MPs secreted by activated PMNs during TEM displayed a high level of enzymatically activematrixmetalloproteinase 9 (MMPâ 9), and were capable of mediating potent effects on IEC integrity. Isolated PMNâ MPs efficiently bound to IEC monolayers and induced cleavage of desmogleinâ 2 (DSGâ 2) but not Eâ cadherin, leading to disruption of IEC intercellular adhesions. Furthermore, PMNâ MP binding to intestinal epithelium in vitro in transwell assays and in vivo in ligated intestinal loop preparations facilitated increases in PMN TEM. These effects were MMPâ 9 dependent and were reversed in the presence of specific pharmacological inhibitors. Finally, we demonstrated that IEC Dsgâ 2 serves as a barrier for migrating PMNs, and its removal by PMNâ MPâ associated MMPâ 9 facilitates PMNtrafficking across epithelial layers. Our findings thus implicate PMNâ MPs in PMNâ mediated inflammation and epithelial damage, as observed in inflammatory disorders ofmucosal surfaces.â Butinâ Israeli, V., Houser, M.C., Feng, M., Thorp, E. B., Nusrat, A., Parkos, C. A, Sumagin, R. Deposition of microparticles by neutrophils onto inflamed epithelium: anewmechanism to disrupt epithelial intercellular adhesions and promote transepithelialmigration. FASEB J. 30, 4007â 4020 (2016). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154234/1/fsb2fasebj30120734r.pd

Lysosome-mediated processing of chromatin in senescence

Cellular senescence is a stable proliferation arrest, a potent tumor suppressor mechanism, and a likely contributor to tissue aging. Cellular senescence involves extensive cellular remodeling, including of chromatin structure. Autophagy and lysosomes are important for recycling of cellular constituents and cell remodeling. Here we show that an autophagy/lysosomal pathway processes chromatin in senescent cells. In senescent cells, lamin A/C–negative, but strongly γ-H2AX–positive and H3K27me3-positive, cytoplasmic chromatin fragments (CCFs) budded off nuclei, and this was associated with lamin B1 down-regulation and the loss of nuclear envelope integrity. In the cytoplasm, CCFs were targeted by the autophagy machinery. Senescent cells exhibited markers of lysosomal-mediated proteolytic processing of histones and were progressively depleted of total histone content in a lysosome-dependent manner. In vivo, depletion of histones correlated with nevus maturation, an established histopathologic parameter associated with proliferation arrest and clinical benignancy. We conclude that senescent cells process their chromatin via an autophagy/lysosomal pathway and that this might contribute to stability of senescence and tumor suppression

Autophagy mediates degradation of nuclear lamina

Z.D. is supported by a fellow award from the Leukemia & Lymphoma Society. B.C.C. is supported by career development awards from the Dermatology Foundation, Melanoma Research Foundation, and American Skin Association. S.L.B., P.D.A. and R.M. are supported by NIA P01 grant (P01AG031862). S.L.B. is also supported by NIH R01 CA078831. R.D.G. is supported by R01 GM106023 and the Progeria Research Foundation

Lamin B1 regulates somatic mutations and progression of B-cell malignancies

Somatic hypermutation (SHM) is a pivotal process in adaptive immunity that occurs in the germinal centre and allows B cells to change their primary DNA sequence and diversify their antigen receptors. Here, we report that genome binding of Lamin B1, a component of the nuclear envelope involved in epigenetic chromatin regulation, is reduced during B-cell activation and formation of lymphoid germinal centres. Chromatin immunoprecipitation-Seq analysis showed that kappa and heavy variable immunoglobulin domains were released from the Lamin B1 suppressive environment when SHM was induced in B cells. RNA interference-mediated reduction of Lamin B1 resulted in spontaneous SHM as well as kappa-light chain aberrant surface expression. Finally, Lamin B1 expression level correlated with progression-free and overall survival in chronic lymphocytic leukaemia, and was strongly involved in the transformation of follicular lymphoma. In summary, here we report that Lamin B1 is a negative epigenetic regulator of SHM in normal B-cells and a 'mutational gatekeeper', suppressing the aberrant mutations that drive lymphoid malignancy

DNA-Free Recombinant SV40 Capsids Protect Mice from Acute Renal Failure by Inducing Stress Response, Survival Pathway and Apoptotic Arrest

Viruses induce signaling and host defense during infection. Employing these natural trigger mechanisms to combat organ or tissue failure is hampered by harmful effects of most viruses. Here we demonstrate that SV40 empty capsids (Virus Like Particles-VLPs), with no DNA, induce host Hsp/c70 and Akt-1 survival pathways, key players in cellular survival mechanisms. We postulated that this signaling might protect against organ damage in vivo. Acute kidney injury (AKI) was chosen as target. AKI is critical, prevalent disorder in humans, caused by nephrotoxic agents, sepsis or ischemia, via apoptosis/necrosis of renal tubular cells, with high morbidity and mortality. Systemic administration of VLPs activated Akt-1 and upregulated Hsp/c70 in vivo. Experiments in mercury-induced AKI mouse model demonstrated that apoptosis, oxidative stress and toxic renal failure were significantly attenuated by pretreatment with capsids prior to the mercury insult. Survival rate increased from 12% to >60%, with wide dose response. This study demonstrates that SV40 VLPs, devoid of DNA, may potentially be used as prophylactic agent for AKI. We anticipate that these finding may be projected to a wide range of organ failure, using empty capsids of SV40 as well as other viruses

Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143740/1/hep29522.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143740/2/hep29522-sup-0001-suppinfo1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143740/3/hep29522_am.pd

Nuclear Actin and Lamins in Viral Infections

Lamins are the best characterized cytoskeletal components of the cell nucleus that help to maintain the nuclear shape and participate in diverse nuclear processes including replication or transcription. Nuclear actin is now widely accepted to be another cytoskeletal protein present in the nucleus that fulfills important functions in the gene expression. Some viruses replicating in the nucleus evolved the ability to interact with and probably utilize nuclear actin for their replication, e.g., for the assembly and transport of capsids or mRNA export. On the other hand, lamins play a role in the propagation of other viruses since nuclear lamina may represent a barrier for virions entering or escaping the nucleus. This review will summarize the current knowledge about the roles of nuclear actin and lamins in viral infections

Neutrophil-derived microRNAs put the (DNA) breaks on intestinal mucosal healing

A predominant feature of intestinal inflammation is the accumulation of neutrophils, which dictates a fine balance between epithelial repair or progression to chronic inflammation. While the processes of mucosal healing are well studied, how neutrophils advance an inflammatory insult towards epithelial neoplasia is less understood. In this issue of the JCI, Butin-Israeli et al. outline a mechanism whereby neutrophils control epithelial fitness and genomic instability via delivery of miR-23a–and miR-155–containing microparticles. Localized delivery of antisense oligonucleotides targeting miR-23a and miR-155 reversed this genomic instability and accelerated mucosal healing. This mechanism of neutrophil-derived microRNA shuttling opens up new therapeutic potential to enhance epithelial healing and limit mucosal injury