Histamine H2 Receptor Signaling in the Pathogenesis of Sepsis: Studies in a Murine Diabetes Model

Abstract

Type 1 diabetes enhances susceptibility to infection and favors the sepsis development. In addition, diabetic mice produced higher levels of histamine in several tissues and in the blood after LPS stimulation than nondiabetic mice. In this study, we aimed to explore the role of mast cells (MCs) and histamine in neutrophil migration and, consequently, infection control in diabetic mice with mild sepsis (MS) induced by cecum ligation and puncture. We used female BALB/c, MC-sufficient (WB/B6), MC-deficient (W/Wv), and NOD mice. Diabetic mice given MS displayed 100% mortality within 24 h, whereas all nondiabetic mice survived for at least 5 d. The mortality rate of diabetic mice was reduced to 57% after the depletion of MC granules with compound 48/80. Moreover, this pretreatment increased neutrophil migration to the focus of infection, which reduced systemic inflammatory response and bacteremia. The downregulation of CXCR2 and upregulation of G protein–coupled receptor kinase 2 in neutrophils was prevented by pretreatment of diabetic mice given MS with compound 48/80. In addition, blocking the histamine H2 receptor restored neutrophil migration, enhanced CXCR2 expression, decreased bacteremia, and improved sepsis survival in alloxan-induced diabetic and spontaneous NOD mice. Finally, diabetic W/Wv mice had neutrophil migration to the peritoneal cavity, increased CXCR2 expression, and reduced bacteremia compared with diabetic WB/B6 mice. These results demonstrate that histamine released by MCs reduces diabetic host resistance to septic peritonitis in mice.

Neutrophil Function Impairment Is a Host Susceptibility Factor to Bacterial Infection in Diabetes

“…After septic stimuli, T1DM mice exhibited mast cell accumulation in the peritoneal cavity and higher plasma levels of histamine than nondiabetic mice. In addition, the augmented activation of H2 receptor promoted an increase in intracellular expression of GRK2 and cAMP levels in diabetic septic mice neutrophils, favoring CXCR2 desensitization [74].…”

“…However, some evidence has shown that histamine can modulate other immunological events. Neutrophils express both histamine receptors, H1 and H2 [74] and activation of H2 inhibited human neutrophil chemotaxis in vitro [75]. Furthermore, blood neutrophils obtained after systemic or inhalatory administration of histamine in normal volunteers showed a reduction in chemotactic response to zymosan in vitro [75].…”

“…T1DM or T2DM animals have worse prognosis upon CLP-induced sepsis even though plasma levels of systemic proinflammatory cytokines, like TNF-α, CXCL2/MIP-2, and IL-6, are increased in diabetic animals compared with control animals upon sepsis induction. This situation is normally attributed to neutrophil dampened activity [48,74,89,90].…”

Effect of gastric acid suppressants and prokinetics on peritoneal dialysis-related peritonitis

“…Histamine, which is released by peritoneal mast cells, stimulates vasodilation and encourages leukocyte transmigration. Moreover, histamine induces the aggregation of complement and opsonin, which promotes bacterial phagocytosis [21][22][23] . H2Bs block these mechanisms and also inhibit inflammation-generated increases in nitric oxide concentrations [24] , resulting in reduced …”

Diabetic Animal Models with Infectious Diseases: Focus on the Dysfunction of Immune System

“…The same research team recently demonstrated that mast cells also participate in the increased susceptibility of diabetic mice to septic peritonitis. Specifically, the histamine released by mast cells appears to impair neutrophil migration through histamine H 2 receptor signaling [46].…”