Biology subjects

Nigrovic, P.

Publications and source records attributed to Nigrovic, P..

3 recordsLinked to original sources

bioRxiv2019

The organization of leukotriene biosynthesis on the nuclear envelope revealed by single molecule localization microscopy and computational analyses

The initial steps in the synthesis of leukotrienes are the translocation of 5-lipoxygenase (5-LO) to the nuclear envelope and its subsequent association with its scaffold protein 5-lipoxygenase-activating protein (FLAP). A major gap in our understanding of this process is the knowledge of how the organization of 5-LO and FLAP on the nuclear envelope regulates leukotriene synthesis. We combined single molecule localization microscopy with Clus-DoC cluster analysis, and also a novel unbiased cluster analysis to analyze changes in the relationships between 5-LO and FLAP in response to activation of RBL-2H3 cells to generate leukotriene C4. We identified the time-dependent reorganization of both 5-LO and FLAP into higher-order assemblies or clusters in response to cell activation via the IgE receptor. Clus-DoC analysis identified a subset of these clusters with a high degree of interaction between 5-LO and FLAP that specifically correlates with the time course of LTC4 synthesis, strongly suggesting their role in the initiation of leukotriene biosynthesis.

cell biology↗

bioRxiv2018

Differential attenuation of β2 integrin-dependent and -independent neutrophil migration by Ly6G ligation

Abstract\n\nAntibody ligation of the murine neutrophil surface protein Ly6G disrupts neutrophil migration in some contexts but not others. We tested whether this variability reflected divergent dependence of neutrophil migration on {beta}2 integrins, adhesion molecules that interact with Ly6G at the neutrophil surface. In integrin-dependent murine arthritis, Ly6G ligation attenuated joint inflammation, even though mice lacking Ly6G altogether developed arthritis normally. By contrast, Ly6G ligation had no impact on integrin- independent neutrophil migration into inflamed lung. In peritoneum, the role of {beta}2 integrins varied with stimulus, proving dispensable for neutrophil entry in E. coli peritonitis but contributory in IL-1-mediated sterile peritonitis. Correspondingly, Ly6G ligation attenuated only IL-1 peritonitis, disrupting the molecular association between integrins and Ly6G and inducing cell-intrinsic blockade restricted to integrin-dependent migration. Consistent with this observation, Ly6G ligation impaired integrin-mediated postadhesion strengthening for neutrophils arresting on activated cremaster endothelium in vivo. Together, these findings identify selective inhibition of integrin- mediated neutrophil emigration through Ly6G ligation, highlighting the marked site and stimulus specificity of {beta}2 integrin dependence in neutrophil migration.\n\nKEY POINTSO_LIThe contribution of {beta}2 integrins to neutrophil migration into inflamed tissues varies with site and stimulus.\nC_LIO_LILigation of Ly6G, a GPI-linked neutrophil surface protein, selectively attenuates {beta}2 integrin-dependent neutrophil migration in vivo.\nC_LIO_LIBlockade correlates with disrupted interaction between Ly6G and {beta}2 integrins and impaired integrin-mediated postadhesion strengthening.\nC_LI

immunology↗

bioRxiv2017

Fine-mapping identifies causal variants for RA and T1D in DNASE1L3, SIRPG, MEG3, TNFAIP3 and CD28/CTLA4 loci

We fine-mapped 76 rheumatoid arthritis (RA) and type 1 diabetes (T1D) loci outside of the MHC. After sequencing 799 1kb regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We fine-mapped1,2 these loci in RA (11,475 cases, 15,870 controls)3, T1D (9,334 cases and 11,111 controls) 4 and combined datasets. We reduced the number of potential causal variants to [≤]5 in 8 RA and 11 T1D loci. We identified causal missense variants in five loci (DNASE1L3, SIRPG, PTPN22, SH2B3 and TYK2) and likely causal non-coding variants in six loci (MEG3, TNFAIP3, CD28/CTLA4, ANKRD55, IL2RA, REL/PUS10). Functional analysis confirmed allele specific binding and differential enhancer activity for three variants: the CD28/CTLA4 rs117701653 SNP, the TNFAIP3 rs35926684 indel, and the MEG3 rs34552516 indel. This study demonstrates the potential for dense genotyping and imputation to pinpoint missense and non-coding causal alleles.

genetics↗