Endotoxin- and ATP-neutralizing activity of alkaline phosphatase as a strategy to limit neuroinflammation

Abstract

BackgroundAlkaline phosphatase (AP) is a ubiquitously expressed enzyme which can neutralize endotoxin as well as adenosine triphosphate (ATP), an endogenous danger signal released during brain injury. In this study we assessed a potential therapeutic role for AP in inhibiting neuroinflammation using three complementary approaches.MethodsMice were immunized to induce experimental autoimmune encephalomyelitis (EAE) and treated with AP for seven days during different phases of disease. In addition, serological assays to determine AP activity, endotoxin levels and endotoxin-reactive antibodies were performed in a cohort of multiple sclerosis (MS) patients and controls. Finally, the expression of AP and related enzymes CD39 and CD73 was investigated in brain tissue from MS patients and control subjects.ResultsAP administration during the priming phase, but not during later stages, of EAE significantly reduced neurological signs. This was accompanied by reduced proliferation of splenocytes to the immunogen, myelin oligodendrocyte glycoprotein peptide. In MS patients, AP activity and isoenzyme distribution were similar to controls. Although endotoxin-reactive IgM was reduced in primary-progressive MS patients, plasma endotoxin levels were not different between groups. Finally, unlike AP and CD73, CD39 was highly upregulated on microglia in white matter lesions of patients with MS.ConclusionsOur findings demonstrate that: 1) pre-symptomatic AP treatment reduces neurological signs of EAE; 2) MS patients do not have altered circulating levels of AP or endotoxin; and 3) the expression of the AP-like enzyme CD39 is increased on microglia in white matter lesions of MS patients.

CD73 is expressed by inflammatory Th17 cells in experimental autoimmune encephalomyelitis but does not limit differentiation or pathogenesis

“…However, mice deficient in the receptor for the CD73 product adenosine develop severe EAE with exaggerated cytokine responses[17, 18]. We were therefore surprised to find that CD73 -/- mice did not develop exacerbated disease signs following EAE induction.…”

Intestinal alkaline phosphatase: novel functions and protective effects

“…Importantly, oral IAP administration was able to stimulate endogenous IAP in the small intestine but had no effect on the colonic TNAP isoform . Administration of exogenous IAP stimulated the release of endogenous TNAP isoform into the systemic circulation in patients undergoing cardiac vascular surgery but not in the brain of mice . However, the pathophysiological significance of TNAP isoform induction in these studies is unclear.…”

“…Administration of exogenous IAP was also found to be protective in patients undergoing coronary artery bypass surgery, and exogenous IAP reduced neurological alterations in a model of autoimmune encephalomyelitis in mice …”

“…Administration of exogenous IAP has been shown to reduce systemic inflammation in various animal models and in several diseases in humans (Table ), as demonstrated in NEC, peritonitis, sepsis, and even brain disease …”

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

“…The production of IL-1β by amoeboid microglia increased oligodendrocyte injury in the periventricular white matter of rats following neonatal hypoxia [191] and perinatal IL-1β exposure induced ventricular enlargement, increased the loss of mature oligodendrocytes, and produced white matter injury in rats [192]. Neutralization of ATP, an important ligand for P2X7, during the acute injury phase reduced neurological injury after EAE, which is characterized by widespread white matter loss [193]. Consistent with these reports, administration of the selective microglial inhibitor, minocycline, attenuated microglial activation, decreased IL-1β production, protected developing oligodendrocytes, and attenuated white matter injury in neonatal rat brains [194, 195].…”