Role of Pentraxin-3 in Periodontal Inflammation - A Comprehensive Review

Acute phase reactants like C-reactive protein (CRP), and pentraxin 3 (PTX3) are increased with inflammation and tissue injury. PTX3 is an acute phase protein and a member of the long pentraxin family. CRP is synthesized in the liver but PTX3 is generated locally at the inflammatory site. It is a fluid-phase pattern-recognition molecule that regulates antimicrobial immunity and inflammation by interfering with selectin-dependent neutrophil recruitment and regulating the complement cascade. Hence, PTX3 could be used as a potential biomarker to identify inflammatory response in both acute and chronic diseases. In this review, we discuss the role of PTX3 in periodontal inflammation.

Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates

Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. We here analyze the single-cell transcriptome of >16,000 Tregs obtained from peripheral blood and synovial fluid of two patients with HLA-B27+ ankylosing spondylitis and three patients with psoriatic arthritis, closely related forms of inflammatory spondyloarthritis. We identify multiple Treg clusters with distinct transcriptomic profiles, including, among others, a regulatory CD8+ subset expressing cytotoxic markers/genes, and a Th17-like RORC+ Treg subset characterized by IL-10 and LAG-3 expression. Synovial Tregs show upregulation of interferon signature and TNF receptor superfamily genes, and marked clonal expansion, consistent with tissue adaptation and antigen contact respectively. Individual synovial Treg clones map to different clusters indicating cell fate divergence. Finally, we demonstrate that LAG-3 directly inhibits IL-12/23 and TNF secretion by patient-derived monocytes, a mechanism with translational potential in SpA. Our detailed characterization of Tregs at an important inflammatory site illustrates the marked specialization of Treg subpopulations.

Microfluidic Systems to Study Neutrophil Forward and Reverse Migration

During infection, neutrophils are the most abundantly recruited innate immune cells at sites of infection, playing critical roles in the elimination of local infection and healing of the injury. Neutrophils are considered to be short-lived effector cells that undergo cell death at infection sites and in damaged tissues. However, recent in vitro and in vivo evidence suggests that neutrophil behavior is more complex and that they can migrate away from the inflammatory site back into the vasculature following the resolution of inflammation. Microfluidic devices have contributed to an improved understanding of the interaction and behavior of neutrophils ex vivo in 2D and 3D microenvironments. The role of reverse migration and its contribution to the resolution of inflammation remains unclear. In this review, we will provide a summary of the current applications of microfluidic devices to investigate neutrophil behavior and interactions with other immune cells with a focus on forward and reverse migration in neutrophils.

New Insight into Molecular and Hormonal Connection in Andrology

Hormones and cytokines are known to regulate cellular functions in the testes. These biomolecules induce a broad spectrum of effects on various level of spermatogenesis, and among them is the modulation of cell junction restructuring between Sertoli cells and germ cells in the seminiferous epithelium. Cytokines and androgens are closely related, and both correct testicular development and the maintenance of spermatogenesis depend on their function. Cytokines also play a crucial role in the immune testicular system, activating and directing leucocytes across the endothelial barrier to the inflammatory site, as well as in increasing their adhesion to the vascular wall. The purpose of this review is to revise the most recent findings on molecular mechanisms that play a key role in male sexual function, focusing on three specific molecular patterns, namely, cytokines, miRNAs, and endothelial progenitor cells. Numerous reports on the interactions between the immune and endocrine systems can be found in the literature. However, there is not yet a multi-approach review of the literature underlying the role between molecular patterns and testicular and sexual function.

Synergistic regulation mechanism of selectin and integrin on leukocyte adhesion under shear flow

In the process of inflammation, the hydrodynamic process of circulating leukocyte recruitment to the inflammatory site requires the rolling adhesion of leukocytes in blood vessels mediated by selectin and integrin molecules. Although a number of experiments have demonstrated that cooperative effects exist between selectins and integrins in leukocyte rolling adhesion under shear flow, the mechanisms underlying how the mechanics of selectins and integrins synergistically may govern the dynamics of cell rolling is not yet fully resolved. Here we present a mechanical model on selectin- and integrin- jointly mediated rolling adhesion of leukocyte in shear flow, by considering two pairs' binding/unbinding events as Markov processes and describing kinetics of leukocyte by the approach of continuum mechanics. Through examining the dynamics of leukocyte rolling as a function of relative fraction of selectin and integrin pairs, we show that, during recruitment, the elongation of intermittent weak selectin bonds consuming the kinetic energy of rolling leukocyte decelerates the rolling speed and enables the integrin pairs to form strong bonds, therefore achieving the arrestment of leukocyte (firm adhesion). The coexistence of selectins and integrins may also be required for effective phase transition from firm adhesion to rolling adhesion, due to dynamic competition in pairs' formation and elongation. These results are verified by the relevant Monte Carlo simulations and related to reported experimental observations.

TET1 controls Cxcl1 induction by DNA demethylation and promotes neutrophil recruitment during acute lung injury

Neutrophils are rapidly recruited from the peripheral blood to the inflammatory site to initiate inflammatory response against pathogenic infections. The process to recruit neutrophils must be properly regulated since the abnormal accumulation of neutrophils can cause organ damage and dysfunction. The acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a common cause of respiratory failure that is characterized by the infiltration of neutrophils and epithelial integrity disruption. Indeed, recent studies suggest a pathogenic role of neutrophils in the clinic severity of the coronavirus disease 2019 (COVID-19) ARDS. The chemokine CXCL1, which is rapidly induced by inflammatory stimuli, plays a key role in neutrophil influx during lung inflammation. The molecular basis of Cxcl1 induction is not fully understood. Here we report that TET1, a member of the ten eleven translocation (TET) methylcytosine dioxygenase protein family, displays a striking specificity in the regulation of gene expression in macrophages. RNA sequencing (RNA-seq) analysis showed that Tet1 disruption significantly altered the expression of only 48 genes that include Cxcl1 and several other genes known to be important for cell migration and trafficking in bone marrow derived macrophages (BMDMs) in response to LPS stimulation. TET1 regulates the induction of Cxcl1 by facilitating the DNA demethylation of the Cxcl1 promoter. In Tet1−/− mice, the induction of Cxcl1 was suppressed, resulting in defective neutrophil recruitment to the lung during LPS-induced acute lung injury. Our results identify a novel epigenetic mechanism that selectively controls Cxcl1 induction and neutrophil recruitment during acute lung injury.Key PointsTET1 has a striking specificity in macrophage gene regulation and controls Cxcl1 induction by inflammatory stimuli via DNA demethylationNeutrophil recruitment is defective in Tet1 deficient mice during acute lung injury

Biomechanical forces enhance directed migration and activation of bone marrow-derived dendritic cells

Mechanical forces are pervasive in the inflammatory site where dendritic cells (DCs) are activated to migrate into draining lymph nodes. For example, fluid shear stress modulates the movement patterns of DCs, including directness and forward migration indices (FMIs), without chemokine effects. However, little is known about the effects of biomechanical forces on the activation of DCs. Accordingly, here we fabricated a microfluidics system to assess how biomechanical forces affect the migration and activity of DCs during inflammation. Based on the structure of edema, we proposed and experimentally analyzed a novel concept for a microchip model that mimicked such vascular architecture. The intensity of shear stress generated in our engineered chip was found as 0.2–0.6 dyne/cm2 by computational simulation; this value corresponded to inflammation in tissues. In this platform, the directness and FMIs of DCs were significantly increased, whereas the migration velocity of DCs was not altered by shear stress, indicating that mechanical stimuli influenced DC migration. Moreover, DCs with shear stress showed increased expression of the DC activation markers MHC class I and CD86 compared with DCs under static conditions. Taken together, these data suggest that the biomechanical forces are important to regulate the migration and activity of DCs.

Single cell analysis of spondyloarthritis regulatory T cells identifies distinct synovial gene expression patterns and clonal fates

Regulatory T cells (Tregs) play an important role in controlling inflammation and limiting autoimmunity, but their phenotypes at inflammatory sites in human disease are poorly understood. We here analyze the single-cell transcriptome of >16,000 Tregs obtained from peripheral blood and synovial fluid of two patients with HLA-B27+ ankylosing spondylitis and three patients with psoriatic arthritis, closely related forms of inflammatory spondyloarthritis. We identify multiple Treg clusters with distinct transcriptomic profiles, including, among others, a regulatory CD8+ subset expressing cytotoxic markers/genes, and a Th17-like RORC+ Treg subset characterized by IL-10 and LAG-3 expression. Synovial Tregs show upregulation of interferon signature and TNF receptor superfamily genes, and marked clonal expansion, consistent with tissue adaptation and antigen contact respectively. Individual synovial Treg clones map to different clusters indicating cell fate divergence. Finally, we demonstrate that LAG-3 directly inhibits IL-12/23 and TNF secretion by patient-derived monocytes, a mechanism with translational potential in SpA. Our detailed characterization of Tregs at an important inflammatory site illustrates the marked specialization of Treg subpopulations.

Differential mast cell numbers and characteristics in human tuberculosis pulmonary lesions

Tuberculosis (TB) is still a major worldwide health threat and primarily a lung disease. The innate immune response against Mycobacterium tuberculosis (Mtb) is orchestrated by dendritic cells, macrophages, neutrophils, natural killer cells and apparently mast cells (MCs). MCs are located at mucosal sites including the lungs and contribute in host-defence against pathogens, but little is known about their role during Mtb infection. This study investigates the location and characteristics of MCs in TB lesions to assess their contribution to TB pathology. To this purpose, number, location and phenotype of MCs was studied in 11 necropsies of pulmonary TB and 3 necropsies of non-TB infected lungs that were used as controls. MCs were localised at pneumonic areas, in the granuloma periphery and particularly abundant in fibrotic tissue. Furthermore, MCs displayed intracellular Mtb and IL-17A and TGF-β immunostaining. These findings were validated by analysing, post-mortem lung tissue microarrays from 44 individuals with pulmonary TB and 25 control subjects. In affected lungs, increased numbers of MCs expressing intracellularly both tryptase and chymase were found at fibrotic sites. Altogether, our data suggest that MCs are recruited at the inflammatory site and that actively produce immune mediators such as proteases and TGF-β that may be contributing to late fibrosis in TB lesions.