Integrated pathways for neutrophil recruitment and inflammation in leprosy.
Neutrophil recruitment is pivotal to the host defense against microbial infection, but it also contributes to the immunopathology of disease. We investigated the mechanism of neutrophil recruitment in human infectious disease by means of 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 and is characterized by neutrophil infiltration in lesions, the most overrepresented biological functional group was cell movement, including E-selectin, which was coordinately regulated with interleukin 1beta (IL-1beta). In vitro activation of Toll-like receptor 2 (TLR2), up-regulated in ENL lesions, triggered induction of IL-1beta, which together with interferon 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 and Fc receptor activation, neutrophil migration, and inflammation, providing insight into mechanisms of neutrophil recruitment in human infectious disease.
Lee
Delphine J
DJ
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles 90095, USA. dellee@mednet.ucla.edu
Li
Huiying
H
Ochoa
Maria T
MT
Tanaka
Motoyuki
M
Carbone
Ryan J
RJ
Damoiseaux
Robert
R
Burdick
Anne
A
Sarno
Euzenir N
EN
Rea
Thomas H
TH
Modlin
Robert L
RL
D016000:Cluster Analysis; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D007918:Leprosy / Q000235:genetics / Q000276:immunology*; D008954:Models, Biological; D009167:Mycobacterium lepraemurium / Q000302:isolation & purification; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D011961:Receptors, Fc / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000276:immunology / Q000382:microbiology; D013792:Thalidomide / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
D019040:E-Selectin; D053583:Interleukin-1beta; D011961:Receptors, Fc; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D013792:Thalidomide; D007371:Interferon-gamma