Awadhesh K. Arya

Immune mediators are elevated due to carbon monoxide (CO) poisoning but their role in the development of neurological deficits is unknown. Circulating microparticles (MPs) are elevated in response to CO and correlate with the development of neurological complications. We hypothesized that interleukin (IL)-1β is carried by MPs and contributes to the development of neurological sequelae (NS). Blood-borne IL-1β in CO-poisoned patients is almost exclusively carried by MPs. Healthy humans have 0.8 ± 0.8 (n = 27) MPs/μL bearing IL-1β on the membrane surface. IL-1β-bearing MPs obtained from patients at the time of CO poisoning diagnosis who recover (Global Deterioration Score [GDS] = 1 at 1 month) numbered 35 ± 12/μL (n = 27, p < 0.001 vs. control) and patients who sustained NS (GDS > 1 at 1 month) had 75 ± 38/μL (n = 27; p < 0.001 vs. control and CO-recovered groups). Twice as many MPs carry IL-1β cargo as express surface-bearing IL-1β. The concentration is higher post-CO but does not correlate with NS. Those with NS have 43.8 ± 42.0 pg IL-1β /10⁶ MPs, and those with GDS = 1 have 33.0 ± 32.0 pg/10⁶ MPs, versus controls 5.4 ± 0.3 pg/10⁶ MPs, p < 0.001. In a murine CO model, MPs IL-1β cargo follows similar proportions to humans. Pharmacologic blockade of IL-1β using an IL-1 receptor antagonist or neutralizing anti-IL-1β antibody inhibited neuroinflammation and preserved neurological function. Results demonstrate that brain-derived MPs liberated via the glymphatic system to the peripheral circulation activate neutrophils which are the prime generators of IL-1β-bearing MPs that maintain a cycle of neuroinflammation. Targeting IL-1β disrupts MP-mediated inflammation.

CO-induced neuroinflammation requires endothelial CD36 engagement of circulating microparticles that trigger neutrophil vascular adherence, neuroinflammation, and a transient elevation of glymphatic flow, establishing a self-perpetuating neuroinflammatory cycle.

Elevated glymphatic flow, glial cell activation, increased circulating microparticles (MPs), and neutrophil activation due to decompression have been well documented in animal models. This report shows that filamentous (F)-actin expressing MPs produced postdecompression interact with endothelial CD36 driving a feed-forward neuroinflammatory cycle and inducing vascular injury.

The mechanism for neurological deficits from carbon monoxide (CO) poisoning is unclear. In a series of 150 patients with CO poisoning, we found marked elevations of blood-borne inflammatory filamentous (F-) actin–coated microparticles (MPs), neutrophil activation, and a 90% reduction in the normal level of plasma gelsolin (pGSN), a protein capable of lysing F-actin–coated MPs. This led to studies in a murine model where the same events occur and cause neuroinflammation with cognitive dysfunction. All events are recapitulated when F-actin MPs are injected intravenously, which establishes a blood-to-brain-to-blood inflammatory cycle that persists for weeks. All changes, including cognitive dysfunction, can be abrogated by an injection of human recombinant pGSN within 2 weeks after CO poisoning. These findings demonstrate that CO-induced neurological injury has an inflammatory etiology. Because of MP-mediated communications between the brain and systemic circulation, CO-induced cognitive deficits may be reversible with a pharmaceutical intervention.

A decrease in plasma gelsolin levels and the release of inflammatory microparticles (MPs) occur in response to high pressure followed by decompression, with expression of filamentous (F)-actin leading to persistent neuroinflammation and functional deficits lasting at least 12 days. The infusion of recombinant human plasma gelsolin lyses these MPs in decompressed mice, thereby alleviating particle-associated neuronal dysfunction. Rhu-gelsolin infusion may be beneficial as a prophylactic or treatment for decompression sickness.

We hypothesized that early intra-CNS responses in a murine model of decompression sickness (DCS) would be reflected by changes in the microparticles (MPs) that exit the brain via the glymphatic system, and due to systemic responses the MPs would cause inflammatory changes lasting for many days leading to functional neurological deficits. Elevations on the order of 3-fold of blood-borne inflammatory MPs, neutrophil activation, glymphatic flow and neuroinflammation in cerebral cortex and hippocampus were found in mice at 12 days after exposure to 760 kPa of air for 2 hours. Mice also exhibited a significant decline in memory and locomotor activity, as assessed by novel object recognition and rotarod testing. Similar inflammatory changes in blood, neuroinflammation and functional impairments were initiated in naïve mice by injection of filamentous (F-) actin-positiveMPs, but not F-actin-negative MPs,obtained from decompressed mice. We conclude that high pressure/decompression stress establishes a systemic inflammatory process that results in prolonged neuroinflammation and functional impairments in the mouse decompression model.

The Cancers Editorial Office retracts the article entitled ‘Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia’

A blood component analysis is an early step for evaluating inflammatory disorders, but it can be unfeasible in some settings. This pilot study assessed whether extracellular vesicle (EV) changes in perspiration are parallel to those occurring in blood as an alternative or complementary option to diagnose an inflammatory response. In parallel studies, EVs were analyzed in perspiration and blood obtained before and after five self-contained underwater breathing apparatus (SCUBA) divers at the National Aquarium in Baltimore performed a dive to 3.98 m of sea water for 40 min, and five non-divers performed an exercise routine at ambient atmospheric pressure. The results demonstrated that microparticles (MPs) are present in perspiration, their numbers increase in the blood in response to SCUBA diving, and the interleukin (IL)-1β content increases. In contrast, while blood-borne MPs became elevated in response to terrestrial exercise, no statistically significant increases occurred in perspiration, and there were no changes in IL-1β. There were no statistically significant elevations in the exosomes in perspiration or blood in response to SCUBA diving and few changes following terrestrial exercise. These findings suggest that an MP perspiration analysis could be a non-invasive method for detecting inflammatory responses that can occur due to the oxidative stress associated with SCUBA diving.

The T cell lineage–restricted protein THEMIS plays a critical role in T cell development at the positive selection stage. In the SHP1 activation model, THEMIS is proposed to enhance the activity of the tyrosine phosphatase SHP1 (encoded by Ptpn6 ), thereby dampening T cell antigen receptor (TCR) signaling and preventing the inappropriate negative selection of CD4 ⁺ CD8 ⁺ thymocytes by positively selecting ligands. In contrast, in the SHP1 inhibition model, THEMIS is proposed to suppress SHP1 activity, rendering CD4 ⁺ CD8 ⁺ thymocytes more sensitive to TCR signaling initiated by low-affinity ligands to promote positive selection. We sought to resolve the controversy regarding the molecular function of THEMIS. We found that the defect in positive selection in Themis ^−/− thymocytes was ameliorated by pharmacologic inhibition of SHP1 or by deletion of Ptpn6 and was exacerbated by SHP1 overexpression. Moreover, overexpression of SHP1 phenocopied the Themis ^−/− developmental defect, whereas deletion of Ptpn6 , Ptpn11 (encoding SHP2), or both did not result in a phenotype resembling that of Themis deficiency. Last, we found that thymocyte negative selection was not enhanced but was instead impaired in the absence of THEMIS. Together, these results provide evidence favoring the SHP1 inhibition model, supporting a mechanism whereby THEMIS functions to enhance the sensitivity of CD4 ⁺ CD8 ⁺ thymocytes to TCR signaling, enabling positive selection by low-affinity, self-ligand–TCR interactions.

The T-lineage restricted protein THEMIS has been shown to play a critical role in T cell development. THEMIS, via its distinctive CABIT domains, inhibits the catalytic activity of the tyrosine phosphatase SHP1 (PTPN6). SHP1 and THEMIS bind to the ubiquitous cytosolic adapter GRB2, and the purported formation of a tri-molecular THEMIS–GRB2–SHP1 complex facilitates inactivation of SHP1 by THEMIS. The importance of this function of GRB2 among its numerous documented activities is unclear as GRB2 binds to multiple proteins and participates in several signaling responses in thymocytes. Here, we show that similar to Themis−/− thymocytes, the primary molecular defect in GRB2-deficient thymocytes is increased catalytically active SHP1 and the developmental block in GRB2-deficient thymocytes is alleviated by deletion or inhibition of SHP1 and is exacerbated by SHP1 overexpression. Thus, the principal role of GRB2 during T cell development is to promote THEMIS-mediated inactivation of SHP1 thereby enhancing the sensitivity of TCR signaling in CD4+CD8+ thymocytes to low affinity positively selecting self-ligands.