Anti-inflammatory role of fetuin-A in injury and infection

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.

Figure 1. Protective roles of fetuin-A in endotoxemia and sepsis

In response to lethal endotoxemia or sepsis, innate immune cells (such as macrophages) sequentially release early (e.g., TNF and IFN-γ) and late (e.g., HMGB1) proinflammatory mediators. Early proinflammatory cytokines participate in the down-regulation of hepatic fetuin-A expression, allowing propagation of a rigorous inflammatory response manifested by excess accumulation of late proinflammatory mediators (such as HMGB1). On the other hand, HMGB1 stimulates hepatic fetuin-A expression, thereby restoring circulating fetuin-A levels during a late stage of lethal endotoxemia and sepsis. Fetuin-A functions as a negative regulator of the innate immune response by inhibiting LPS- or IFN-γ-induced HMGB1 release in macrophages. Adapted from doi:10.1371/journal.pone.0016945.g006 with granted permission from the publisher.

Figure 2. Protective roles of fetuin-A in cerebral ischemic injury

Cerebral ischemia causes rapid primary injury in the ischemic core, leading to HMGB1 release/leakage. Extracellular HMGB1 then diffuses into the periphery region, where it orchestrates a rigorous inflammatory response driven both by the centrally- and peripherally-derived cells. In parallel, cerebral ischemia induces transient increase in blood-brain barrier permeability, allowing entry of circulating proteins (e.g., fetuin-A) and peripheral immune cells (such as macrophage/monocytes). Peripheral administration of fetuin-A attenuates ischemia-elicited HMGB1 release and subsequent cytokine expression, thereby conferring a temporal protection against cerebral ischemic injury.

Figure 3. Divergent roles of spermine in cerebral ischemic injury