Biology subjects

Joshi, J. C.

Publications and source records attributed to Joshi, J. C..

3 recordsLinked to original sources

bioRxiv2023

RGS2 is an innate immune checkpoint for TLR4 and Gαq-mediated IFNγ generation and lung injury

IFN{gamma}, a type II interferon secreted by immune cells, augments tissue responses to injury following pathogenic infections leading to lethal acute lung injury (ALI). Alveolar macrophages (AM) abundantly express Toll-like receptor-4 and represent the primary cell type of the innate immune system in the lungs. A fundamental question remains whether AM generation of IFNg leads to uncontrolled innate response and perpetuated lung injury. LPS induced a sustained increase in IFNg levels and unresolvable inflammatory lung injury in the mice lacking RGS2 but not in RGS2 null chimeric mice receiving WT bone marrow or receiving the RGS2 gene in AM. Thus, indicating RGS2 serves as a gatekeeper of IFNg levels in AM and thereby lungs innate immune response. RGS2 functioned by forming a complex with TLR4 shielding Gaq from inducing IFNg generation and AM inflammatory signaling. Thus, inhibition of Gaq blocked IFNg generation and subverted AM transcriptome from being inflammatory to reparative type in RGS2 null mice, resolving lung injury. HighlightsO_LIRGS2 levels are inversely correlated with IFN{gamma} in ARDS patients AM. C_LIO_LIRGS2 in alveolar macrophages regulate the inflammatory lung injury. C_LIO_LIDuring pathogenic insult RGS2 functioned by forming a complex with TLR4 shielding Gq from inducing IFN{gamma} generation and AM inflammatory signaling. C_LI eToc BlurbAuthors demonstrate an essential role of RGS2 in macrophages in airspace to promoting anti-inflammatory function of alveolar macrophages in lung injury. The authors provided new insight into the dynamic control of innate immune response by Gq and RGS2 axis to prevent ALI.

immunology↗

bioRxiv2023

Tension sensing by FAK governs nuclear mechanotransduction, endothelial transcriptome and fate

Vascular endothelium forms a restrictive barrier to defend the underlying tissue against uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Using endothelial cell (EC)-Fak-/-mice, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK- deleted EC, increased EC tension induced by Rho kinase caused tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Activated emerin stimulated DNMT3a activity and methylation of the KLF2 promoter, impairing the restrictive EC transcriptome, including S1PR1. Inhibiting emerin phosphorylation or DNMT3a activity enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype in EC-Fak-/- lungs. Thus, FAK sensing of tension transmission to the nucleus is crucial for maintaining a restrictive EC fate and lung homeostasis.

cell biology↗

bioRxiv2021

Computer-Vision Stabilized Intravital Imaging Reveals Lung Capillary Neutrophil Dynamics Crucial for Lung Host-Defense Function

Polymorphonuclear neutrophils (PMN) are highly dynamic innate immune cells which are essential for lung host defense. However, in vivo intravital imaging in moving organs such as the lung remains challenging due to motion artifacts. Here we describe a novel intravital imaging method with high-throughput analytical capability based on a computer vision stabilization algorithm, Computer-vision-Assisted STabilized intravital imaging (CASTii). The sub-micron precision of this approach enables analysis of compartmentalized intravital PMN dynamics. We quantified in real-time a novel patrolling function of lung intracapillary circulating PMN. We also describe the dynamics of intracapillary PMN pooling (marginated PMN pool) using direct imaging of PMNs. The pool was formed by repeated catch-and-release kinetics involving PMN deformation inside microvessels during the passage of PMNs in vessels. We observed rapid PMN recruitment into the lung tissue compartments from pooled PMNs in response to alveolar chemoattract exposure. In contrast, endotoxemia-induced intracapillary sequestration of PMN impaired PMN transmigration into the alveolar space and defective phagocytosis of live bacteria. Intravital imaging of PMN dynamics with CASTii provides fundamental insights into host-defense functions of lung capillary PMN.

microbiology↗