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Integrated pathways for neutrophil recruitment and inflammation in leprosy

ABSTRACT: Neutrophil recruitment is pivotal to host defense against microbial infection, but also contributes to the immunopathology of disease. We investigated the mechanism of neutrophil recruitment in human infectious disease by bioinformatic pathways analysis of the gene expression profiles in the skin lesions of leprosy. In erythema nodosum leprosum (ENL), which occurs in patients with lepromatous leprosy (L-lep), and is characterized by neutrophil infiltration in lesions, the most overrepresented biologic functional group was 'cell movement' including E-selectin, which was coordinately regulated with IL-1beta. In vitro activation of TLR2, upregulated in ENL lesions, triggered induction of IL-1beta, which together with IFN-gamma, induced E-selectin expression on, and neutrophil adhesion to endothelial cells. Thalidomide, an effective treatment for ENL, inhibited this neutrophil recruitment pathway. The gene expression profile of ENL lesions comprised an integrated pathway of TLR2/FcR activation, neutrophil migration and inflammation, providing insight into mechanisms of neutrophil recruitment in human infectious disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE16844 | GEO | 2009/06/30

SECONDARY ACCESSION(S): PRJNA117615

REPOSITORIES: GEO

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Integrated pathways for neutrophil recruitment and inflammation in leprosy

Project description:Neutrophil recruitment is pivotal to host defense against microbial infection, but also contributes to the immunopathology of disease. We investigated the mechanism of neutrophil recruitment in human infectious disease by bioinformatic pathways analysis of the gene expression profiles in the skin lesions of leprosy. In erythema nodosum leprosum (ENL), which occurs in patients with lepromatous leprosy (L-lep), and is characterized by neutrophil infiltration in lesions, the most overrepresented biologic functional group was “cell movement” including E-selectin, which was coordinately regulated with IL-1. In vitro activation of TLR2, upregulated in ENL lesions, triggered induction of IL-1, which together with IFN-, induced E-selectin expression on, and neutrophil adhesion to endothelial cells. Thalidomide, an effective treatment for ENL, inhibited this neutrophil recruitment pathway. The gene expression profile of ENL lesions comprised an integrated pathway of TLR2/FcR activation, neutrophil migration and inflammation, providing insight into mechanisms of neutrophil recruitment in human infectious disease. 6 ENL skin lesions and 7 Lepromatous leprosy skin lesions

2009-06-30 | E-GEOD-16844 | biostudies-arrayexpress

Integration of cell type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy

Project description:Transcriptome profiles derived from the site of human disease has led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene co-expression modules by cell type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach towards identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease.

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Genomewide expression profiling from peripheral blood of multibacillary leprosy and Erythema Nodosum Leprosum (ENL) before and after thalidomide treatment.

Project description:Acute inflammatory episodes are common in leprosy and complicate the course of the disease. Among these episodes, Erythema Nodosum Leprosum (ENL) is more common in multibacillary patients and can cause more systemic symptoms like fever, myalgia, edema, and pain. Today, ENL is managed with thalidomide and corticosteroids, yet the exact mechanisms behind ENL remain elusive and with few pharmacological options available. In this experiment, RNA was sequenced and gene expression was measured from the blood of multibacillary patients with and without ENL in a mixed design, comparing ENL to MB and ENL before and after thalidomide treatment for 7 days.

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Project description:Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis of S. aureus-infected skin revealed that induction of neutrophil recruitment genes was largely dependent upon IL-1beta/IL-1R activation. Unexpectedly, using IL 1beta reporter mice, neutrophils were identified as the primary source of IL-1beta at the site of infection. Furthermore, IL-1beta-producing neutrophils were necessary and sufficient for abscess formation and bacterial clearance. S. aureus-induced IL 1beta production by neutrophils required TLR2, NOD2, FPRs and the ASC/NLRP3 inflammasome. Taken together, IL-1beta and neutrophil abscess formation during an infection are functionally, spatially and temporally linked as a consequence of direct IL-1beta production by neutrophils.

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Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice

2012-12-05 | E-GEOD-36826 | biostudies-arrayexpress

Homo sapiens

Project description:Integrated pathways for neutrophil recruitment and inflammation in leprosy

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miRNA expression profile in leprosy skin biopsy specimens

Project description:Skin biopsy specimens of skin lesions were profiled for miRNA expression. In this study, we indentified miRNA species that were differentially expressed in the skin lesions of either the lepromatous or tuberculoid forms of leprosy. One miRNA species, hsa-mir-21, found in the lepromatous lesions was capable of downregulating the vitamin D-dependent antimicrobial pathway. Scalpel or punch skin biopsy specimens were obtained after informed consent from patients with tuberculoid leprosy and patients with lepromatous leprosy at the time of diagnosis. Specimens were embedded in OCT medium, snap-frozen in liquid nitrogen and stored at 80°C until sectioning.

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Genomewide expression profiling from peripheral blood of multibacillary leprosy and Erythema Nodosum Leprosum (ENL) before and after thalidomide treatment.

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