Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis

Krishnan, Nitya; Gilman, Robert Hugh; Porter, Joanna C.; Kirwan, Daniela E.; López, José W.; Friedland, Jon S.; Fox, Katharine A.; Whittington, Ashley M.; Robertson, Brian D.; Singh, Shivani

dc.contributor.author	Fox, Katharine A.
dc.contributor.author	Kirwan, Daniela E.
dc.contributor.author	Whittington, Ashley M.
dc.contributor.author	Krishnan, Nitya
dc.contributor.author	Robertson, Brian D.
dc.contributor.author	Gilman, Robert Hugh
dc.contributor.author	López, José W.
dc.contributor.author	Singh, Shivani
dc.contributor.author	Porter, Joanna C.
dc.contributor.author	Friedland, Jon S.
dc.date.accessioned	2018-11-30T22:50:35Z
dc.date.available	2018-11-30T22:50:35Z
dc.date.issued	2018
dc.identifier.uri	https://hdl.handle.net/20.500.12866/4152
dc.description.abstract	RATIONALE: Platelets may interact with the immune system in tuberculosis (TB) to regulate human inflammatory responses that lead to morbidity and spread of infection. OBJECTIVES: To identify a functional role of platelets in the innate inflammatory and matrix-degrading response in TB. METHODS: Markers of platelet activation were examined in plasma from 50 patients with TB before treatment and 50 control subjects. Twenty-five patients were followed longitudinally. Platelet-monocyte interactions were studied in a coculture model infected with live, virulent Mycobacterium tuberculosis (M.tb) and dissected using qRT-PCR, Luminex multiplex arrays, matrix degradation assays, and colony counts. Immunohistochemistry detected CD41 (cluster of differentiation 41) expression in a pulmonary TB murine model, and secreted platelet factors were measured in BAL fluid from 15 patients with TB and matched control subjects. MEASUREMENTS AND MAIN RESULTS: Five of six platelet-associated mediators were upregulated in plasma of patients with TB compared with control subjects, with concentrations returning to baseline by Day 60 of treatment. Gene expression of the monocyte collagenase MMP-1 (matrix metalloproteinase-1) was upregulated by platelets in M.tb infection. Platelets also enhanced M.tb-induced MMP-1 and -10 secretion, which drove type I collagen degradation. Platelets increased monocyte IL-1 and IL-10 and decreased IL-12 and MDC (monocyte-derived chemokine; also known as CCL-22) secretion, as consistent with an M2 monocyte phenotype. Monocyte killing of intracellular M.tb was decreased. In the lung, platelets were detected in a TB mouse model, and secreted platelet mediators were upregulated in human BAL fluid and correlated with MMP and IL-1β concentrations. CONCLUSIONS: Platelets drive a proinflammatory, tissue-degrading phenotype in TB.	en_US
dc.language.iso	eng
dc.publisher	American Thoracic Society
dc.relation.ispartofseries	American Journal of Respiratory and Critical Care Medicine
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject	tuberculosis	en_US
dc.subject	human	en_US
dc.subject	innate immunity	en_US
dc.subject	matrix metalloproteinases	en_US
dc.subject	platelets	en_US
dc.title	Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis	en_US
dc.type	info:eu-repo/semantics/article
dc.identifier.doi	https://doi.org/10.1164/rccm.201710-2102OC
dc.subject.ocde	https://purl.org/pe-repo/ocde/ford#3.02.07
dc.subject.ocde	https://purl.org/pe-repo/ocde/ford#3.02.08
dc.relation.issn	1535-4970