Journal of immunobiology最新文献

Chronic inflammation plays a major role in impaired healing of diabetic wounds. Mounting evidence highlights the role of controlled, sequential polarization of macrophages in producing the appropriate progression through the stages of wound healing: inflammation (pro- inflammatory stage), proliferation and remodeling (regenerative stage). Non-coding RNAs, including microRNAs, maintain critical roles in regulating normal biological processes, such as wound healing; and are being explored as therapeutic targets for modulating dysfunction in disease states. Interestingly, microRNA-21 (miR-21) has a suggested role in the induction of pro-inflammatory and regenerative stages of healing, but clarity remains elusive on the specific mechanisms determining the direction miR-21 shifts wound healing processes. Findings by Liechty et al. in International Journal of Molecular Science indicate an important role of miR-21, in shaping the wound healing cascade by preferentially inducing M1-like (pro-inflammatory) polarization of macrophages in the early phase of diabetic wound healing. Persistent elevation of miR-21 is suggestive of sustained pro-inflammatory drive, and subsequent wound healing impairment, in the skin of diabetic murine models and diabetic human skin. Differences in the expression patterns of miR-21 during diabetic wound healing identifies the potentially critical role of therapeutic timing, for miR-21 based therapies, in driving positive outcomes for patients.

Shortages in the availability of transplantable organs have forced the transplant community to seek alternative methods to increase the supply of available organs. In our recent study following α-1,3-galactocyltransferase knockout (GalT-KO) pig-to-baboon kidney xenotransplantation, we found that certain recipients developed increased serum creatinine, possibly due to the rapid growth of orthotopic pig grafts in smaller baboon recipients. To test our hypothesis, we assessed whether the growth of outbred (Yorkshire) organ transplants (kidney and lung) in miniature swine was regulated by intrinsic (graft) factors. Yorkshire kidneys reached 3.7× their initial volume over 3 months vs. 1.2× for miniature swine kidneys over a similar time period. A similar pattern was seen in porcine lung allografts as well. Following xenotransplantation, a review of our results suggests that there is a threshold for kidney graft volume of 25 cm³/kg of recipient body weight at which cortical ischemia is induced in transplanted GalT-KO kidneys in baboons. These results suggest that intrinsic factors are in part responsible for the growth of donor organs and this should be taken into consideration for growth-curve-mismatched transplants.

Objective: Secretory granules (SG) and lipid bodies (LB) are the primary organelles that mediate functional responses in mast cells. SG contains histamine and matrix-active proteases, while LB are reservoirs of arachidonic acid and its metabolites, precursors for rapid synthesis of eicosanoids such as LTC₄. Both of these compartments can be dynamically or ontologically regulated, with metabolic and immunological stimuli altering lipid body content and granule numbers responding to contextual signals from tissue. We previously described that chronic in vitro or in vivo hyperinsulinemia expands the LB compartment with a concomitant loss of SG capacity, suggesting that this ratio is dynamically regulated. The objective of the current study is to determine if chronic insulin exposure initiates a transcriptional program that biases model mast cells towards a lipogenic state with accompanying loss of secretory granule biogenesis.

Methods: We used a basophilic leukemic cell line with mucosal mast cell-like features as a model system. We tested the hypothesis that chronic insulin exposure initiates a transcriptional program that biases these model mast cells towards a lipogenic state with accompanying loss of secretory granule biogenesis. Transcriptional arrays were used to map gene expression patterns. Biochemical, immunocytochemical and mediator release assays were used to evaluate organelle numbers and functional responses.

Results: In a mucosal mast cell model, the rat basophilic leukemia line RBL2H3, mast cell granularity and SG numbers are inversely correlated with LB numbers. Chronic insulin exposure appears to modulate gene networks involved in both lipid body biogenesis and secretory granule formation. Western blot analysis confirms upregulation of protein levels for LB proteins, and decreases in proteins that are markers for SG cargo.

Conclusions: The levels of insulin in the extracellular milieu may modify the phenotype of mast cell-like cells in vitro.