The Role of Hyaluronan Degradation Products as Innate Alloimmune Agonists

Abstract

Dendritic cells (DCs) play a key role in initiating alloimmunity yet the substances that activate them during the host response to transplantation remain elusive. In this study we examined the potential roles of endogenous innate immune agonists in activating dendritic cell-dependent alloimmunity. Using a murine in vitro culture system, we show that 135 KDa fragments of the extracellular matrix glycosaminoglycan hyaluronan induce dendritic cell maturation and initiate alloimmunity. Priming of alloimmunity by hyaluronan-activated DCs was dependent on signaling via TIR-associated protein, a Toll-like receptor (TLR) adaptor downstream of TLRs 2 and 4. However, this effect was independent of alternate TLR adaptors, MyD88 or Trif. Using an in vivo murine transplant model, we show that hyaluronan accumulated during skin transplant rejection. Examination of human lung transplant recipients demonstrated that increased levels of intragraft hyaluronan were associated with bronchiolitis obliterans syndrome. In conclusion, our study suggests that fragments of hyaluronan can act as innate immune agonists that activate alloimmunity.

The Innate Immune System in Allograft Rejection and Tolerance

“…For example, a recombinant preparation of heat-shock protein 70 with as little as 0.2 ng/ml LPS contamination was found to induce proinflammatory cytokine release from mouse macrophages while a rigorously purified preparation did not (41). Nevertheless, more recent studies (31,32,35) have been designed to specifically address contamination as confounder, substantially strengthening these observations. Furthermore, Tsung et al (42) demonstrate that HMGB1 levels are increased in liver ischemia/reperfusion as early as 1 h after reperfusion, and neutralization of HMGB1 with Ab decreases markers of liver inflammation.…”

“…Several studies have focused on the specific products of necrotic cells or extracellular matrix disruption as a source of danger signals, particularly through TLR2-and TLR4-dependent responses (9,30). Such putative endogenous danger-associated molecules include hyaluronan (31,32), heparan sulfate (33), fibronectin extra domain A (34), and biglycan (35). Additionally, heat-shock proteins 60, 70, and gp96, as well as HMGB1, have been implicated in signaling danger through TLRs (36 -39).…”

Inhibition of Hyaluronan Synthesis Protects against Central Nervous System (CNS) Autoimmunity and Increases CXCL12 Expression in the Inflamed CNS

“…4MU inhibits hyaluronan synthesis in a dose-dependent manner by two mechanisms: depletion of cellular UDP-glucuronic acid and down-regulation of hyaluronan synthases 2 and 3 (14). Importantly, 4MU has no effect on the synthesis of any other glyco- 1 To whom correspondence should be addressed: Tisch MS Research Center of New York, 521 W. 57th St., 4th Fl., New York, NY 10019. Tel.…”

“…Hyaluronan is degraded by a family of enzymes called hyaluronidases. In humans, there are at least seven types of hyaluronidase-like enzymes (1).…”

Role of innate immunity in tolerance induction

“…Некоторые исследования фокусировались на специфических продуктах некротических клеток или разрушении экстрацеллюлярного матрикса как источнике сигналов опасности, особенно через TLR2-и TLR4-зависимый ответы [8,[37][38][39]. Такие предполагаемые эндогенные молекулы, ассоциирующиеся с опасностью, включают гиалуронан [39][40][41][42], гепаран сульфат [43], фибронектин экстра домен F [44] и бигликан [45]. Кроме того, белки теплового шока 60,70 и gp 96, также как и HMGB1, были причастны к сигнализации об опасности через TLRs [46][47][48][49].…”