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In response to tissue injury, changes in the extracellular matrix (ECM) can directly affect the inflammatory response and contribute to disease progression or resolution. During inflammation, the glycosaminoglycan hyaluronan (HA) becomes modified by tumor necrosis factor stimulated gene-6 (TSG6). TSG6 covalently transfers heavy chain (HC) proteins from inter-α-trypsin inhibitor (IαI) to HA in a transesterification reaction and is to date is the only known HC-transferase. By modifying the HA matrix, TSG6 generates HC:HA complexes that are implicated in mediating both protective and pathological responses. Inflammatory bowel disease (IBD) is a lifelong chronic disorder with well-described remodeling of the ECM and increased mononuclear leukocyte influx into the intestinal mucosa. Deposition of HC:HA matrices is an early event in inflamed gut tissue that precedes and promotes leukocyte infiltration. However, the mechanisms by which TSG6 contributes to intestinal inflammation are not well understood. The aim of our study was to understand how the TSG6 and its enzymatic activity contributes to the inflammatory response in colitis. Our findings indicate that inflamed tissues of IBD patients show an elevated level of TSG6 and increased HC deposition and that levels of HA strongly associate with TSG6 levels in patient colon tissue specimens. Additionally, we observed that mice lacking TSG6 are more vulnerable to acute colitis and exhibit an aggravated macrophage-associated mucosal immune response characterized by elevated pro-inflammatory cytokines and chemokines and diminished anti-inflammatory mediators including IL-10. Surprisingly, along with significantly increased levels of inflammation in the absence of TSG6, tissue HA levels in mice were found to be significantly reduced and disorganized, absent of typical "HA-cable" structures. Inhibition of TSG6 HC-transferase activity leads to a loss of cell surface HA and leukocyte adhesion, indicating that the enzymatic functions of TSG6 are a major contributor to stability of the HA ECM during inflammation. Finally, using biochemically generated HC:HA matrices derived by TSG6, we show that HC:HA complexes can attenuate the inflammatory response of activated monocytes. In conclusion, our data suggests that TSG6 exerts a tissue-protective, anti-inflammatory effect via the generation of HC:HA complexes that become dysregulated in IBD., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Neutrophil extracellular traps (NETs) clear pathogens but may contribute Q8 pathogenically to host inflammatory tissue damage during sepsis. Innovative therapeutic agents targeting NET formation and their potentially harmful collateral effects remain understudied., Methods: We investigated a novel therapeutic agent, neonatal NET-Inhibitory Factor (nNIF), in a mouse model of experimental sepsis - cecal ligation and puncture (CLP). We administered 2 doses of nNIF (1 mg/ kg) or its scrambled peptide control intravenously 4 and 10 hours after CLP treatment and assessed survival, peritoneal fluid and plasma NET formation using the MPO-DNA ELISA, aerobic bacterial colony forming units (CFU) using serial dilution and culture, peritoneal fluid and stool microbiomes using 16S rRNA gene sequencing, and inflammatory cytokine levels using a multiplexed cytokine array. Meropenem (25 mg/kg) treatment served as a clinically relevant treatment for infection., Results: We observed increased 6-day survival rates in nNIF (73%) and meropenem (80%) treated mice compared to controls (0%). nNIF decreased NET formation compared to controls, while meropenem did not impact NET formation. nNIF treatment led to increased peritoneal fluid and plasma bacterial CFUs consistent with loss of NET-mediated extracellular microbial killing, while nNIF treatment alone did not alter the peritoneal fluid and stool microbiomes compared to vehicle-treated CLP mice. nNIF treatment also decreased peritoneal TNF-a inflammatory cytokine levels compared to scrambled peptide control. Furthermore, adjunctive nNIF increased survival in a model of sub-optimal meropenem treatment (90% v 40%) in CLP-treated mice., Discussion: Thus, our data demonstrate that nNIF inhibits NET formation in a translationally relevant mouse model of sepsis, improves survival when given as monotherapy or as an adjuvant with antibiotics, and may play an important protective role in sepsis., Competing Interests: CY authors a US patent (patent no. 10,232,023 B2) held by the University of Utah for the use of NET-inhibitory peptides for the “treatment of and prophylaxis against inflammatory disorders,” for which Peel Therapeutics, Inc. holds the exclusive license. JS is shareholder and employed by Peel Therapeutics, Inc. The authors declare that this study received funding from Peel Therapeutics, Inc. in the form of a sponsored research agreement. The funder had the following involvement in the study: through co-author JS, help writing portions of this article., (Copyright © 2023 de Araujo, Denorme, Stephens, Li, Cody, Crandell, Petrey, Queisser, Rustad, Evangelista, Kay, Schiffman, Campbell and Yost.)

Intercellular communication is critical for homeostasis in mammalian systems, including the gastrointestinal (GI) tract. Exosomes are nanoscale lipid extracellular vesicles that mediate communication between many cell types. Notably, the roles of immune cell exosomes in regulating GI homeostasis and inflammation are largely uncharacterized. By generating mouse strains deficient in cell-specific exosome production, we demonstrate deletion of the small GTPase Rab27A in CD11c+ cells exacerbated murine colitis, which was reversible through administration of DC-derived exosomes. Profiling RNAs within colon exosomes revealed a distinct subset of miRNAs carried by colon- and DC-derived exosomes. Among antiinflammatory exosomal miRNAs, miR-146a was transferred from gut immune cells to myeloid and T cells through a Rab27-dependent mechanism, targeting Traf6, IRAK-1, and NLRP3 in macrophages. Further, we have identified a potentially novel mode of exosome-mediated DC and macrophage crosstalk that is capable of skewing gut macrophages toward an antiinflammatory phenotype. Assessing clinical samples, RAB27A, select miRNAs, and RNA-binding proteins that load exosomal miRNAs were dysregulated in ulcerative colitis patient samples, consistent with our preclinical mouse model findings. Together, our work reveals an exosome-mediated regulatory mechanism underlying gut inflammation and paves the way for potential use of miRNA-containing exosomes as a novel therapeutic for inflammatory bowel disease.

Coronavirus disease 2019 (COVID-19) encompasses a broad spectrum of clinical manifestations caused by infection with severe acute respiratory syndrome coronavirus 2.Patients with severe disease present with hyperinflammation which can affect multiple organs which often include observations of microvascular and macrovascular thrombi. COVID-19 is increasingly recognized as a thromboinflammatory disease where alterations of both coagulation and platelets are closely linked to mortality and clinical outcomes. Although platelets are most well known as central mediators of hemostasis, they possess chemotactic molecules, cytokines, and adhesion molecules that are now appreciated as playing an important role in the regulation of immune response. This review summarizes the current knowledge of platelet alterations observed in the context of COVID-19 and their impact upon disease pathobiology., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Hyaluronan (HA) is a polysaccharide found in all tissues as an integral component of the extracellular matrix (ECM) that plays a central regulatory role in inflammation. In fact, HA matrices are increasingly considered as a barometer of inflammation. A number of proteins specifically recognize the HA structure and these interactions modify cell behavior and control the stability of the ECM. Moreover, inflamed airways are remarkably rich with HA and are associated with various inflammatory diseases including cystic fibrosis, influenza, sepsis, and more recently coronavirus disease 2019 (COVID-19). COVID-19 is a worldwide pandemic caused by a novel coronavirus called SARS-CoV-2, and infected individuals have a wide range of disease manifestations ranging from asymptomatic to severe illness. Critically ill COVID-19 patient cases are frequently complicated by development of acute respiratory distress syndrome (ARDS), which typically leads to poor outcomes with high mortality rate. In general, ARDS is characterized by poor oxygenation accompanied with severe lung inflammation, damage, and vascular leakage and has been suggested to be linked to an accumulation of HA within the airways. Here, we provide a succinct overview of known inflammatory mechanisms regulated by HA in general, and those both observed and postulated in critically ill patients with COVID-19.