Title:Anti-Inflammatory Role of Fetuin-A in Injury and Infection
VOLUME: 12 ISSUE: 5
Author(s):H. Wang and A. E. Sama
Affiliation:Department of Emergency Medicine, North Shore University Hospital, North Shore- LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA.
Keywords:Acute phase protein, cerebral ischemic injury, DAMP, endotoxemia, HMGB1, innate immune cells,
PAMP, sepsis.
Abstract:Infection and injury are two seemingly unrelated processes that often converge on common innate
inflammatory responses mediated by pathogen- or damage-associated molecular patterns (PAMPs or
DAMPs). If dysregulated, an excessive inflammation manifested by the overproduction and release of
proinflammatory mediators (e.g., TNF, IFN-γ, and HMGB1) may adversely lead to many pathogenic
consequences. As a counter-regulatory mechanism, the liver strategically re-prioritizes the synthesis and
systemic release of acute phase proteins (APP) including the fetuin-A (also termed alpha-2-HS-glycoprotein for
the human homologue). Fetuin-A is divergently regulated by different proinflammatory mediators, and functions
as a positive or negative APP in injury and infection. It not only facilitates anti-inflammatory actions of cationic
polyamines (e.g., spermine), but also directly inhibits PAMP-induced HMGB1 release by innate immune cells.
Peripheral administration of fetuin-A promotes a short-term reduction of cerebral ischemic injury, but confers a
long-lasting protection against lethal endotoxemia. Furthermore, delayed administration of fetuin-A rescues
mice from lethal sepsis even when the first dose is given 24 hours post the onset of disease. Collectively,
these findings have reinforced an essential role for fetuin-A in counter-regulating injury- or infection-elicited
inflammatory responses.
