Journal
JOURNAL OF INNATE IMMUNITY
Volume 9, Issue 3, Pages 300-317Publisher
KARGER
DOI: 10.1159/000452951
Keywords
Histone; Biological response; Phagocyte; Toll-like receptor; Cytokine release
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Funding
- National Institutes of Health, USA [GM-29507, GM-61656]
- Department of Pathology, University of Michigan Medical School
- UMMS Department of Pathology flow cytometry core facility
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Histones invoke strong proinflammatory responses in many different organs and cells. We assessed biological responses to purified or recombinant histones, using human and murine phagocytes and mouse lungs. H1 had the strongest ability in vitro to induce cell swelling independent of requirements for toll-like receptors (TLRs) 2 or 4. These responses were also associated with lactate dehydrogenase release. H3 and H2B were the strongest inducers of [Ca2+] i elevations in phagocytes. Cytokine and chemokine release from mouse and human phagocytes was predominately a function of H2A and H2B. Double TLR2 and TLR4 knockout (KO) mice had dramatically reduced cytokine release induced in macrophages exposed to individual histones. In contrast, macrophages from single TLR-KO mice showed few inhibitory effects on cytokine production. Using the NLRP3 inflamma-some protocol, release of mature IL-1 beta was predominantly a feature of H1. Acute lung injury following the airway delivery of histones suggested that H1, H2A, and H2B were linked to alveolar leak of albumin and the buildup of polymorphonu-clear neutrophils as well as the release of chemokines and cytokines into bronchoalveolar fluids. These results demonstrate distinct biological roles for individual histones in the context of inflammation biology and the requirement of both TLR2 and TLR4. (C) 2017 S. Karger AG, Basel
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