Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation

Background: The neuroinflammatory response following traumatic brain injury (TBI) is known to be a key secondary injury factor that can drive ongoing neuronal injury. Despite this, treatments that have targeted aspects of the inflammatory pathway have not shown significant efficacy in clinical trials. Main body: We suggest that this may be because classical inflammation only represents part of the story, with activation of neurogenic inflammation potentially one of the key initiating inflammatory events following TBI. Indeed, evidence suggests that the transient receptor potential cation channels (TRP channels), TRPV1 and TRPA1, are polymodal receptors that are activated by a variety of stimuli associated with TBI, including mechanical shear stress, leading to the release of neuropeptides such as substance P (SP). SP augments many aspects of the classical inflammatory response via activation of microglia and astrocytes, degranulation of mast cells, and promoting leukocyte migration. Furthermore, SP may initiate the earliest changes seen in blood-brain barrier (BBB) permeability, namely the increased transcellular transport of plasma proteins via activation of caveolae. This is in line with reports that alterations in transcellular transport are seen first following TBI, prior to decreases in expression of tight-junction proteins such as claudin-5 and occludin. Indeed, the receptor for SP, the tachykinin NK1 receptor, is found in caveolae and its activation following TBI may allow influx of albumin and other plasma proteins which directly augment the inflammatory response by activating astrocytes and microglia. Conclusions: As such, the neurogenic inflammatory response can exacerbate classical inflammation via a positive feedback loop, with classical inflammatory mediators such as bradykinin and prostaglandins then further stimulating TRP receptors. Accordingly, complete inhibition of neuroinflammation following TBI may require the inhibition of both classical and neurogenic inflammatory pathways.Frances Corrigan, Kimberley A. Mander, Anna V. Leonard and Robert Vin

MicroRNAs as Appropriate Discriminators in Non-Specific Alpha-Fetoprotein (AFP) Elevation in Testicular Germ Cell Tumor Patients

Testicular germ cell tumors (TGCTs) are the most commonly diagnosed malignancies in younger men. The monitoring of disease course and recurrence is supported by traditional tumor markers, including α-fetoprotein (AFP). AFP is physiologically synthesized in the liver and can be detected at increased levels in testicular cancer patients as well as under other benign liver diseases, which have been reported as a misleading cause of interpretation of TGCTs clinical course. A cluster of stem cell-associated microRNAs has been reported to outperform traditional tumor markers in newly diagnosed TGCTs, but the value of these microRNAs to differentiate between specific and unspecific AFP elevations, has never been reported. We report here a patient with chronic hepatitis B and normal liver related blood values presenting with a surgically removed primary TGCT and elevated AFP levels. Clinical staging revealed a suspect retroperitoneal metastatic lymph node together with other risk factors and first line treatment with PEB chemotherapy was administered. During curative treatment significantly rising AFP levels led to the assumption of chemo-resistant disease, mandating the initiation of salvage chemotherapy and surgical removal of the putative lymph node metastases. The AFP levels continuously decreased with the interruption of chemotherapeutic agents, indicating a chemotherapy-induced liver toxicity on the basis of pre-existing liver disease. MiR-371a-3p serum levels were not detectable in serum samples with elevated AFP levels. In conclusion, miR-371a-3p may be a reliable biomarker to differentiate between non-specific AFP elevations in TGCTs patients

Neuropeptide substance P and the immune response

Substance P is a peptide mainly secreted by neurons and is involved in many biological processes, including nociception and inflammation. Animal models have provided insights into the biology of this peptide and offered compelling evidence for the importance of substance P in cell-to-cell communication by either paracrine or endocrine signaling. Substance P mediates interactions between neurons and immune cells, with nerve-derived substance P modulating immune cell proliferation rates and cytokine production. Intriguingly, some immune cells have also been found to secrete substance P, which hints at an integral role of substance P in the immune response. These communications play important functional roles in immunity including mobilization, proliferation and modulation of activity of immune cells. This Review summarizes current knowledge of substance P and its receptors, as well as its physiological and pathological roles. We focus on recent developments in the immuno-biology of substance P and we discuss the clinical implications of its ability to modulate the immune response