Editors' ChoiceImmunology

Antibiotics for sickle cell disease

Sci. Signal.  29 Sep 2015:
Vol. 8, Issue 396, pp. ec278
DOI: 10.1126/scisignal.aad5263

Neutrophils are cells of the innate immune system. They are phagocytic cells, which involve activation by the integrin αMβ2 (referred to as Mac-1 activation), and they also form NETS (neutrophil extracellular nets), which capture pathogens in netlike webs. Aged neutrophils are characterized by low abundance of the adhesion molecule L-selectin (referred to as CD62Llo) and high abundance of the chemokine receptor CXCR4 (CXCR4hi). Zhang et al. found an inverse correlation between CD62L abundance and Mac-1 activation–dependent binding of neutrophils to fluorescent beads or binding of red blood cells (RBCs) by adherent neutrophils, suggesting that as neutrophils aged, they became more inflammatory or easily activated. Transcriptomic analysis of aged CD62loCXCR4hi neutrophils compared with control neutrophils revealed that, although the genes associated with some signaling pathways exhibited reduced expression, others, including genes associated with the integrin pathway, Toll-like receptor (TLR) and NOD-like receptor (NLR) pathways, and the nuclear factor κB (NF-κB) pathway exhibited increased expression. Consistent with these transcriptional data, aged neutrophils exhibited increased abundance of TLR4 and molecules associated with migration and intercellular interactions. These data suggested that neutrophils may be continuously exposed to priming signals that progressively increase their potential activity. Microbes in the gut may occasionally breach the epithelial barrier and could be a source of the chronic priming signals that contribute to the properties of aged neutrophils. Indeed, depletion of microbes by prolonged antibiotic treatment of mice resulted in reduced amounts of all neutrophils, and the numbers and proportion of aged neutrophils were decreased. Similar results were obtained without antibiotic treatment for the neutrophil population in germ-free mice and in macrophage-depleted mice, suggesting that depletion of the gut microbiota was important for the antibiotic effect on neutrophil aging and that the reduction in aged neutrophils was not a result of altered macrophage-dependent clearance. Mice in which TLR signaling was compromised by genetic knockout showed reduced numbers and percentages of aged neutrophils. Administration of lipopolysaccharide (LPS) to stimulate TLR4 or a TLR2 agonist, but not a NOD activator, to the antibiotic-treated mice restored the numbers of aged neutrophils in the circulation to higher than that of control mice. Antibiotic treatment also reduced LPS-induced NET formation when the neutrophils were assayed in vitro or in vivo using intravital imaging of mice. Sickle cell disease (SCD) results in deformed RBCs that trigger vascular occlusion, which involves neutrophils and the deformed RBCs. Neutrophils from a mouse model of SCD exhibited an expanded CD62loCXCR4hi neutrophil population with enhanced Mac-1 activation and RBC binding, all of which were reduced to amounts similar to those observed in the control mice upon antibiotic treatment. Furthermore, antibiotic treatment enhanced blood flow, reduced liver damage, and improved the survival of the SCD mice. Comparing populations of immune-compromised patients with SCD that were receiving prophylactic antibiotic treatment with SCD patients that did not receive this treatment revealed that the antibiotic-receiving patients had both lower numbers of total neutrophils and aged neutrophils, which were closer to those in healthy controls. Thus, these data indicate that chronic priming due to microbial breach of the intestine results in a hyperactive aged population of neutrophils, which can be detrimental in patients with neutrophil-mediated vascular disorders.

D. Zhang, G. Chen, D. Manwani, A. Mortha, C. Xu, J. J. Faith, R. D. Burk, Y. Kunisaki, J.-E. Jang, C. Scheiermann, M. Merad, P. S. Frenette, Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015). [PubMed]

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