Abstract
Sepsis is a consequence of systemic bacterial infections leading to hyper activation of immune cells by bacterial products resulting in enhanced release of mediators of inflammation. Endotoxin (LPS) is a major component of the outer membrane of Gram negative bacteria and a critical factor in pathogenesis of sepsis. Development of antagonists that inhibit the storm of inflammatory molecules by blocking Toll like receptors (TLR) has been the main stay of research efforts. We report here that a filarial glycoprotein binds to murine macrophages and human monocytes through TLR4 and activates them through alternate pathway and in the process inhibits LPS mediated classical activation which leads to inflammation associated with endotoxemia. The active component of the nematode glycoprotein mediating alternate activation of macrophages was found to be a carbohydrate residue, Chitohexaose. Murine macrophages and human monocytes up regulated Arginase-1 and released high levels of IL-10 when incubated with chitohexaose. Macrophages of C3H/HeJ mice (non-responsive to LPS) failed to get activated by chitohexaose suggesting that a functional TLR4 is critical for alternate activation of macrophages also. Chitohexaose inhibited LPS induced production of inflammatory molecules TNF-α, IL-1β and IL-6 by macropahges in vitro and in vivo in mice. Intraperitoneal injection of chitohexaose completely protected mice against endotoxemia when challenged with a lethal dose of LPS. Furthermore, Chitohexaose was found to reverse LPS induced endotoxemia in mice even 6/24/48 hrs after its onset. Monocytes of subjects with active filarial infection displayed characteristic alternate activation markers and were refractory to LPS mediated inflammatory activation suggesting an interesting possibility of subjects with filarial infections being less prone to develop of endotoxemia. These observations that innate activation of alternate pathway of macrophages by chtx through TLR4 has offered novel opportunities to cell biologists to study two mutually exclusive activation pathways of macrophages being mediated through a single receptor.
Highlights
Sepsis and septic shock, one of the most common causes of admission in intensive care units results in death of nearly 3, 50,000 people every year only in US and Europe [1,2]
Hyper inflammation induced by bacteria or bacterial products through Toll like receptors leads to sepsis and current approaches are directed towards blockade such receptors
In this study we describe a novel approach to treat endotoxemia associated with sepsis, fundamentally different from other reports
Summary
One of the most common causes of admission in intensive care units results in death of nearly 3, 50,000 people every year only in US and Europe [1,2]. In sepsis caused by Gram-negative bacteria, endotoxin (LPS) activates the immune system through TLR4 and induces activation of macrophages that produce inflammatory mediators [7,8]. LPS forms a complex with LPS binding protein and CD14 which in turn delivers LPS to MD2 and LPS-MD2 complex activates through TLR4 resulting in dimerization of TLR4 [3] and initiate the signaling process for production of cytokines and other critical molecules needed for hyper-inflammation associated with endotoxemia/sepsis [12]
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