Hyperglycemic environments directly compromise intestinal epithelial barrier function in an organoid model and hyaluronan (∼35 kDa) protects via a layilin dependent mechanism.

Background: Metabolic syndrome and diabetes in obese individuals are strong risk factors for development of inflammatory bowel disease (IBD) and colorectal cancer. The pathogenic mechanisms of low-grade metabolic inflammation, including chronic hyperglycemic stress, in disrupting gut homeostasis are poorly understood. In this study, we sought to understand the impact of a hyperglycemic environment on intestinal barrier integrity and the protective effects of small molecular weight (35 kDa) hyaluronan on epithelial barrier function.

Heparin inhibits proinflammatory and promotes anti-inflammatory macrophage polarization under hyperglycemic stress.

Monocytes are rapidly recruited to sites of diabetic complications and differentiate into macrophages. Previously, we showed that rat kidney mesangial cells dividing during hyperglycemic stress abnormally synthesize hyaluronan (HA) in intracellular compartments. This initiates a stress response, resulting in an extracellular HA matrix after division that recruits inflammatory cells.

Heparin affects cytosolic glucose responses of hyperglycemic dividing mesangial cells.

Mesangial expansion underlies diabetic nephropathy, leading to sclerosis and renal failure. The glycosaminoglycan heparin inhibits mesangial cell growth, but the molecular mechanism is unclear. Here, rat mesangial cells (RMCs) were growth-arrested in the G/G phase of cell division, stimulated to divide in normal glucose (5.

Hyaluronan Rafts on Airway Epithelial Cells.

Many cells, including murine airway epithelial cells, respond to a variety of inflammatory stimuli by synthesizing leukocyte-adhesive hyaluronan (HA) cables that remain attached to their cell surfaces. This study shows that air-liquid interface cultures of murine airway epithelial cells (AECs) also actively synthesize and release a majority of their HA onto their ciliated apical surfaces to form a heavy chain hyaluronan (HC-HA) matrix in the absence of inflammatory stimuli. These matrices do not resemble the rope-like HA cables but occur in distinct sheets or rafts that can capture and embed leukocytes from cell suspensions.

The Responses of Hyperglycemic Dividing Mesangial Cells to Heparin Are Mediated by the Non-reducing Terminal Trisaccharide.

Our previous studies showed: (i) that growth-arrested G0/G1 rat mesangial cells stimulated to divide in hyperglycemic medium initiate intracellular hyaluronan synthesis that induces autophagy and the cyclin D3-induced formation of a monocyte-adhesive extracellular hyaluronan matrix after completing cell division; and (ii) that heparin inhibits the intracellular hyaluronan and autophagy responses, but after completing division, induces hyaluronan synthesis at the plasma membrane with the formation of a larger monocyte-adhesive hyaluronan matrix. This study shows: (i) that the non-terminal trisaccharide of heparin is sufficient to initiate the same responses as intact heparin, (ii) that a fully sulfated tetrasaccharide isolated from bacterial heparin lyase 1 digests of heparin that contains a Δ-2S-iduronate on the non-reducing end does not initiate the same responses as intact heparin, and (iii) that removal of the Δ-2S-iduronate to expose the fully sulfated trisaccharide (GlcNS(6S)-IdoUA(2S)-GlcNS(6S)) does initiate the same responses as intact heparin. These results provide evidence that mammalian heparanase digestion of heparin and heparan sulfate exposes a cryptic motif on the non-reducing termini that is recognized by a receptor on dividing cells.

T cell-derived Act1 is necessary for IL-25-mediated Th2 responses and allergic airway inflammation.

The cellular and molecular mechanisms driven by IL-25 and its cognate receptor IL-17RB necessary for the promotion of Th2-mediating pathogenic pulmonary inflammation remains to be defined. We have previously reported the critical role of the U-box-type E3 ubiquitin ligase Act1 (1) for the downstream signaling of the IL-17 cytokine family including the Th2-promoting cytokine IL-25 (IL-17E) (2). In this study, we report that IL-25-driven but not conventional IL-4-driven Th2 polarization and cytokine production is impaired in Act1-deficient T cells.

The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation.

Interleukin 17 (IL-17) is critical in the pathogenesis of inflammatory and autoimmune diseases. Here we report that Act1, the key adaptor for the IL-17 receptor (IL-7R), formed a complex with the inducible kinase IKKi after stimulation with IL-17. Through the use of IKKi-deficient mice, we found that IKKi was required for IL-17-induced expression of genes encoding inflammatory molecules in primary airway epithelial cells, neutrophilia and pulmonary inflammation.