Inflammatory signaling in human tuberculosis granulomas is spatially organized

TY - JOUR

T1 - Inflammatory signaling in human tuberculosis granulomas is spatially organized

AU - Marakalala, Mohlopheni J

AU - Raju, Ravikiran M

AU - Sharma, Kirti

AU - Zhang, Yanjia J

AU - Eugenin, Eliseo A

AU - Prideaux, Brendan

AU - Daudelin, Isaac B

AU - Chen, Pei-Yu

AU - Booty, Matthew G

AU - Kim, Jin Hee

AU - Eum, Seok Yong

AU - Via, Laura E

AU - Behar, Samuel M

AU - Barry, Clifton E

AU - Mann, Matthias

AU - Dartois, Véronique

AU - Rubin, Eric J

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner. Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas have a pro-inflammatory environment that is characterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatory signature. These findings are consistent across a set of six human subjects and in rabbits. Although the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. From the protein and lipid snapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma.

AB - Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner. Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas have a pro-inflammatory environment that is characterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatory signature. These findings are consistent across a set of six human subjects and in rabbits. Although the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. From the protein and lipid snapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma.

KW - Animals

KW - Arachidonic Acid

KW - Eicosanoids

KW - Granuloma

KW - Humans

KW - Immunohistochemistry

KW - Inflammation

KW - Laser Capture Microdissection

KW - Mass Spectrometry

KW - Microscopy, Confocal

KW - Proteomics

KW - Rabbits

KW - Reactive Oxygen Species

KW - Signal Transduction

KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

KW - Tuberculosis, Pulmonary

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, N.I.H., Intramural

KW - Research Support, N.I.H., Extramural

U2 - 10.1038/nm.4073

DO - 10.1038/nm.4073

M3 - Journal article

C2 - 27043495

SN - 1078-8956

VL - 22

SP - 531

EP - 538

JO - Nature Medicine

JF - Nature Medicine

IS - 5

ER -