Mutual regulation of CD4+ T cells and intravascular fibrin in infections.

Innate myeloid cells especially neutrophils and their extracellular traps are known to promote intravascular coagulation and thrombosis formation in infections and various other conditions. Innate myeloid cell dependent fibrin formation can support systemic immunity while its dysregulation enhances the severity of infectious diseases. Less is known about the immune mechanisms preventing dysregulation of fibrin homeostasis in infection. During experimental systemic infections local fibrin deposits in the liver microcirculation cause rapid arrest of CD4+ T cells. Arrested T helper cells mostly represent Th17 cells that partially originate from the small intestine. Intravascular fibrin deposits activate mouse and human CD4+ T cells which can be mediated by direct fibrin - CD4+ T cell interactions. Activated CD4+ T cells suppress fibrin deposition and microvascular thrombosis by directly counteracting coagulation activation by neutrophils and classical monocytes. T cell activation, which is initially triggered by IL- 12p40- and MHC-II dependent mechanisms, enhances intravascular fibrinolysis via LFA-1. Moreover, CD4+ T cells disfavor the association of the fibrinolysis inhibitor TAFI with fibrin whereby fibrin deposition is increased by TAFI in the absence but not presence of T cells. In human infections thrombosis development is inversely related to microvascular levels of CD4+ T cells. Thus, fibrin promotes LFA-1 dependent T helper cell activation in infections which drives a negative feedback cycle that rapidly restricts intravascular fibrin and thrombosis development.

Heterocomplexes between the atypical chemokine MIF and the CXC-motif chemokine CXCL4L1 regulate inflammation and thrombus formation.

To fulfil its orchestration of immune cell trafficking, a network of chemokines and receptors developed that capitalizes on specificity, redundancy, and functional selectivity. The discovery of heteromeric interactions in the chemokine interactome has expanded the complexity within this network. Moreover, some inflammatory mediators, not structurally linked to classical chemokines, bind to chemokine receptors and behave as atypical chemokines (ACKs). We identified macrophage migration inhibitory factor (MIF) as an ACK that binds to chemokine receptors CXCR2 and CXCR4 to promote atherogenic leukocyte recruitment. Here, we hypothesized that chemokine-chemokine interactions extend to ACKs and that MIF forms heterocomplexes with classical chemokines. We tested this hypothesis by using an unbiased chemokine protein array. Platelet chemokine CXCL4L1 (but not its variant CXCL4 or the CXCR2/CXCR4 ligands CXCL8 or CXCL12) was identified as a candidate interactor. MIF/CXCL4L1 complexation was verified by co-immunoprecipitation, surface plasmon-resonance analysis, and microscale thermophoresis, also establishing high-affinity binding. We next determined whether heterocomplex formation modulates inflammatory/atherogenic activities of MIF. Complex formation was observed to inhibit MIF-elicited T-cell chemotaxis as assessed by transwell migration assay and in a 3D-matrix-based live cell-imaging set-up. Heterocomplexation also blocked MIF-triggered migration of microglia in cortical cultures in situ, as well as MIF-mediated monocyte adhesion on aortic endothelial cell monolayers under flow stress conditions. Of note, CXCL4L1 blocked binding of Alexa-MIF to a soluble surrogate of CXCR4 and co-incubation with CXCL4L1 attenuated MIF responses in HEK293-CXCR4 transfectants, indicating that complex formation interferes with MIF/CXCR4 pathways. Because MIF and CXCL4L1 are platelet-derived products, we finally tested their role in platelet activation. Multi-photon microscopy, FLIM-FRET, and proximity-ligation assay visualized heterocomplexes in platelet aggregates and in clinical human thrombus sections obtained from peripheral artery disease (PAD) in patients undergoing thrombectomy. Moreover, heterocomplexes inhibited MIF-stimulated thrombus formation under flow and skewed the lamellipodia phenotype of adhering platelets. Our study establishes a novel molecular interaction that adds to the complexity of the chemokine interactome and chemokine/receptor-network. MIF/CXCL4L1, or more generally, ACK/CXC-motif chemokine heterocomplexes may be target structures that can be exploited to modulate inflammation and thrombosis.

Comparative study on clinical efficacy of different methods for the treatment of intramural aortic hematoma.

To explore the difference of curative effect between different treatment modalities, in order to provide reference for the treatment of aortic intramural hematoma (IMH). 168 patients with aortic intramural hematoma diagnosed and treated from January 2010 to July 2020 were selected in the Second Affiliated Hospital of Nanchang University. Among them, 48 patients were diagnosed with Stanford A aortic intramural hematoma and 120 were diagnosed with Stanford B aortic intramural hematoma. According to the therapeutic methods, patients were divided into conservative treatment group and endovascular treatment group (TEVAR). For endovascular treatment group, according to the different timing of surgery, can be divided into acute phase group (onset within 72 h) and non-acute phase group (time of onset > 72 h).The clinical data and follow-up data were collected and analyzed by variance analysis and χ2 test. There were 168 patients diagnosed with aortic intramural hematoma 39 of them were (81.25%) Stanford A aortic intramural hematoma patients with pleural or pericardial effusion. For patient with Stanford A aortic intramural hematoma, endovascular treatment was performed in 15 patients (31.2%), and 33 cases (68.8%) for conservative treatment. The average follow-up (24.9 ± 13.9) was months. There were 120 patients with Stanford type B aortic intramural hematoma (71.4%), 60 patients received endovascular treatment (50%), and 60 patients (50%) received conservative treatment, with an average follow-up of (27.8 ± 14.6) months. For Stanford A type aortic intramural hematoma patients when the maximum aortic diameter ≥ 50 mm or hematoma thickness ≥ 11 mm, with high morbidity and mortality, positive endovascular treatment can reduce complications and death. For patients with Stanford type B aortic intramural hematoma, when the maximum aortic diameter ≥ 40 mm or hematoma thickness ≥ 10 mm, with high morbidity and mortality, positive endovascular treatment can reduce complications and death. Both Stanford type A and B aortic intramural hematoma patients could benefit from the endovascular treatment when the initial maximum aortic diameter is ≥ 50 mm or the hematoma thickness is ≥ 11 mm.

Familial early-onset deep venous thrombosis associated with a novel HRG mutation.

Deep venous thrombosis (DVT) remains a serious clinical problem that affects millions of people worldwide. Some DVT cases are caused by inherited thrombophilia derived from genetic aberrations and several disease-causing genes have been identified so far. Among them, HRG is an uncommon one with limited related reports. Here, we reported on a family with early-onset DVT where acquired risky conditions were excluded. Whole exome sequencing revealed a novel heterozygous single base pair substitution in exon 2 of HRG gene resulting in a conserved residue replacement of the protein (c. C271T, p. P73S). Sanger sequencing confirmed the co-segregation of the mutation and plasma quantification determined circulating protein deficiency. The mutation might therefore impair hemostatic balance by causing reduced circulating HRG level. Our study broadens the mutation spectrum of the HRG gene and underscores the importance of its function in regulating coagulation pathway.