Endothelial Protein kinase D1 is a major regulator of post-traumatic hyperinflammation

Abstract

Trauma is a major cause of death worldwide. The post-traumatic immune response culminates in the release of pro-inflammatory mediators, translating in the infiltration of neutrophils (PMNs) at injury sites. The extent of this inflammation is determined by multiple factors, such as PMN adhesion to the endothelium, transendothelial migration, endothelial barrier integrity as well as PMN swarming, mass infiltration and activation. This process is initiated by secondary lipid mediators, such as leukotriene B4 (LTB4). We here provide evidence that Protein kinase D1 (PRKD1) in endothelial cells is implicated in all these processes. Endothelial PRKD1 is activated by pro-inflammatory stimuli and amplifies PMN-mediated inflammation by upregulation of cytokine and chemokines as well as adhesion molecules, such as ICAM-1, VCAM-1 and E-selectin. This induces enhanced PMN adhesion and trans-migration. PRKD1 activation also destabilizes endothelial VE-cadherin adhesion complexes and thus the endothelial barrier, fostering PMN infiltration. We even describe a yet unrecognized PRKD1-dependant mechanism to induce biosynthesis of the PMN-swarming mediator LTB4 directed via intercellular communication through small extracellular vesicles (sEVs) and enhanced CXCL8 secretion from activated endothelial cells. These endothelial sEVs transfer the LTB4 biosynthesis enzyme LTA4 hydrolase (LTA4H) to prime PMNs, while initiating biosynthesis also requires additional signals, like CXCL8. We further demonstrate the respective LTA4H-positive sEVs in the serum of polytrauma patients, peaking 12 h post injury. Therefore, PRKD1 is a key regulator in the coordinated communication of the endothelium with PMNs and a vital signaling node during post-traumatic inflammation.

Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice

“…Many of the remaining down-regulated genes have roles in various immune activities (Fig. 5): Prkd1 (Serine/threonine-protein kinase D1), involved in inter alia promoting neutrophil infiltration [106]; S1pr1 (Sphingosine-1-phosphate receptor 1), essential for immune cell trafficking [107]; Coq10b, required for coenzyme Q function [108, 109]; Kcne4 (Potassium voltage-gated channel subfamily E member 4), an immune regulator via modulation of Kv1.3 [110]; Atf3, a stress-inducible transcription factor [111]; Marco, a scavenger receptor [112]; and Thbs1 (thrombospondin), a matricellular protein involved in lung inflammation resolution and repair [113]. Two stress-inducible genes, Atf3 and Hspa1b (a heat shock protein 70 member) were down-regulated, with Atf3 and Hsp70 upregulated in a large range of stress responses [100, 111].…”

Screening and identification of key biomarkers associated with endometriosis using bioinformatics and next generation sequencing data analysis

“…VCAM1 [761], PRKCB (protein kinase C beta) [780], ADRB2 [808], PRKD1 [920], DAPK1 [947], ACTC1 [924] and NFIX (nuclear factor I X) [1660] are found to be associated with cardiovascular diseases. Studies show that VCAM1 [761], SNCA (synuclein alpha) [1026], ADRB2 [1073], FOXQ1 [1044], PRKD1 [1188], DAPK1 [947], ACTC1 [1192], CST1 [1030], NFIB (nuclear factor I B) [1198] and ERG (ETS transcription factor ERG) [1661] are involved in the process of inflammation. VCAM1 [1232] and ADRB2 [969] are an important regulator of the polycystic ovarian syndrome.…”

Single-cell sequencing analysis and multiple machine-learning models revealed the cellular crosstalk of dendritic cells and identified FABP5 and KLRB1 as novel biomarkers for psoriasis

“…To validate the differences observed among the clusters, we conducted a differential expression analysis and identified significant upregulation of LTB, CD52, and TRAC in cluster 1 DCs. These genes have been extensively associated with hyperinflammation (Figure 3D) (20)(21)(22). To gain further insights into the molecular mechanisms driving the observed differences, we performed differential expression analysis of DCs between psoriasis and normal tissues.…”