Histamine Produced by Gram-Negative Bacteria Impairs Neutrophil’s Antimicrobial Response by Engaging the Histamine 2 Receptor

Abstract

We found that histamine (10⁻⁹ M) did not have any effect on the <i>in vitro</i> capture of <i>Escherichia coli</i> by neutrophils but accelerated its intracellular killing. In contrast, histamine (10⁻⁶ M) delayed the capture of <i>Escherichia coli</i> by neutrophils and reduced the amounts of pHrodo zymosan particles inside acidic mature phagosomes. Histamine acted through the H₄R and the H₂R, which are coupled to the Src family tyrosine kinases or the cAMP/protein kinase A pathway, respectively. The protein kinase A inhibitor H-89 abrogated the delay in bacterial capture induced by histamine (10⁻⁶ M) and the Src family tyrosine kinase inhibitor PP2 blocked histamine (10⁻⁹ M) induced acceleration of bacterial intracellular killing and tyrosine phosphorylation of proteins. To investigate the role of histamine in pathogenicity, we designed an <i>Acinetobacter baumannii</i> strain deficient in histamine production (hdc::TOPO). <i>Galleria mellonella</i> larvae inoculated with the wild-type <i>Acinetobacter baumannii</i> ATCC 17978 strain (1.1 × 10⁵ CFU) died rapidly (100% death within 40 h) but not when inoculated with the <i>Acinetobacter baumannii</i> hdc::TOPO mutant (10% mortality). The concentration of histamine rose in the larval haemolymph upon inoculation of the wild type but not the <i>Acinetobacter baumannii</i> hdc::TOPO mutant, such concentration of histamine blocks the ability of hemocytes from <i>Galleria mellonella</i> to capture <i>Candida albicans</i> <i>in vitro</i>. Thus, bacteria-producing histamine, by maintaining high levels of histamine, may impair neutrophil phagocytosis by hijacking the H₂R.