Mice that have been subjected to cecal ligation and puncture (CLP) have an impaired ability to clear a subsequent Pseudomonas aeruginosa challenge compared with that of sham CLP controls. We hypothesized that this outcome is dependent upon a caspase-1 mechanism and tested this hypothesis by measuring caspase-1 after CLP and by measuring clearance of a bacterial challenge in caspase-1-deficient mice after CLP. Wild-type mice subjected to CLP had increased caspase-1 activity as well as increased IL-1β and increased IL-18 production in splenocytes stimulated with heat-killed Pseudomonas and had increased plasma concentrations of IL-1β and IL-18 and impaired clearance of a P. aeruginosa challenge compared with sham controls. Healthy, uninjured caspase-1(-\-) mice did not differ from wild-type mice in their ability to clear a Pseudomonas challenge. However, unlike wild-type mice, caspase-1(-/-) mice subjected to CLP had no impairment of bacterial clearance of the Pseudomonas challenge, suggesting that caspase-1 induction after CLP played a role in impairment of bacterial clearance. This was further substantiated by the use of a specific caspase-1 inhibitor, Ac-YVAD-CMK. Wild-type mice treated with Ac-YVAD-CMK (10 mg/kg s.c. twice daily, initiated at time of CLP) did not have impaired clearance of a Pseudomonas challenge compared with that of sham mice and had significantly improved bacterial clearance compared with that of untreated CLP mice. Increased caspase-1 expression and activity after CLP injury appears to contribute to diminished innate immune function.
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http://dx.doi.org/10.4049/jimmunol.1002102 | DOI Listing |
J Neuroinflammation
January 2025
Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Background: Traumatic brain injury (TBI) is characterized by high mortality and disability rates. Disease-associated microglia (DAM) are a newly discovered subtype of microglia. However, their presence and function in the acute phase of TBI remain unclear.
View Article and Find Full Text PDFJ Immunother Cancer
January 2025
State Key Laboratory of Oncology in South China, and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
Background: The biological significance of MAF1, a tumor suppressor, in carcinogenesis and immune response of hepatocellular carcinoma (HCC) remains unreported. Understanding the underlying mechanisms by which MAF1 enhances anti-tumor immunity in HCC is crucial for developing novel immunotherapy strategies and enhancing clinical responses to treatment for patients with HCC.
Methods: Mice were subjected to hydrodynamic tail vein injections of transposon vectors to overexpress AKT/NRas, or c-Myc, with or without wild-type (WT) or mutant-activated (-4A) MAF1, or short-hairpin MAF1 (shMAF1).
Brain Res
January 2025
Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. Electronic address:
Traumatic brain injury (TBI) can lead to chronic neuroinflammation, and neurodegeneration associated with long-term cognitive deficits. Following TBI, the acute neuroinflammatory response involves microglial activation and the release of proinflammatory cytokines and chemokines which induce the recruitment of peripheral immune cells such as monocytes and ultimately T cells. Persistent innate and adaptive immune cells response can lead to chronic neurodegeneration and functional deficits.
View Article and Find Full Text PDFJ Bone Miner Res
January 2025
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States.
We previously documented successful resolution of skeletal and dental disease in the infantile and late-onset murine models of hypophosphatasia (HPP), with a single injection of an adeno-associated serotype 8 vector encoding mineral-targeted TNAP (AAV8-TNAP-D10). Here, we conducted dosing studies in both HPP mouse models. A single escalating dose from 4x108 up to 4x1010 (vg/b) was intramuscularly injected into 4-day-old Alpl-/- mice (an infantile HPP model) and a single dose from 4x106 up to 4x109 (vg/b) was administered to 8-week-old AlplPrx1/Prx1 mice (a late-onset HPP model).
View Article and Find Full Text PDFJ Thromb Haemost
January 2025
Department of Pathology and Laboratory Medicine; Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kansas City, KS 66160. Electronic address:
Background: A loss-of-functional mutation (W1183R) in human complement factor H (CFH) is associated with complement-associated hemolytic uremic syndrome; mice carrying a similar mutation (W1206R) in CFH also develop thrombotic microangiopathy but its plasma von Willebrand factor (VWF) multimer sizes were dramatically reduced. The mechanism underlying such a dramatic change in plasma VWF multimer distribution in these mice is not fully understood.
Objective And Methods: To determine the VWF and CFH interaction and how CFH proteins affect VWF multimer distribution, we employed recombinant protein expression, purification, and various biochemical and biophysical tools.
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