Abstract
Although the mechanisms for sustained chemokine gradients and recurring cell infiltration in sterile peritonitis have not been elucidated, toll-like receptors (TLRs) have been implicated. To abate the deleterious recruitment of neutrophils in sterile inflammation, we repeatedly administered a TLR7 ligand that hyposensitized to TLR7 and receptors that converged on the MyD88-signaling intermediary and reduced cellular infiltration in murine autoimmune models of multiple sclerosis and arthritis. To reduce potential adverse effects, a polyethylene glycol polymer was covalently attached to the parent compound (Tolerimod1). The proinflammatory potency of Tolerimod1 was 10-fold less than the unconjugated TLR7 ligand, and Tolerimod1 reduced neutrophil recruitment in chemically induced peritonitis and colitis. The effects of Tolerimod1 were mediated by the radioresistant cells in radiation chimeric mice and by mast cells in reconstituted mast cell-deficient mice (Kit W-sh). Although the Tolerimod1 had weak proinflammatory agonist activity, it effectively reduced neutrophil recruitment in sterile peritoneal inflammation.
Highlights
The inflammatory response is a major host defense mechanism to prevent infection or to repair injury [1]
We previously demonstrated that the repeated administration of a TLR7 ligand ameliorated joint inflammation in the K/BxN serum-transferred arthritis model and reduced inflammatory cell influx in the EAE model [6]
We previously demonstrated that repeated administration of an unconjugated TLR7 ligand (1V136) reduced joint inflammation in the neutrophil-dependent K/BxN serum transfer arthritis model [6]
Summary
The inflammatory response is a major host defense mechanism to prevent infection or to repair injury [1]. In the context of sterile inflammation the perpetual recruitment of neutrophils into the local environment can lead to deleterious sequelae from proteases and other products released from their granules [2]. Chronicity is established when sustained levels of chemokines attract the influx of neutrophils and monocytes. Disruption of this recurring cycle and reduction of neutrophil recruitment could suppress subsequent infiltration of other types of immune cells and could prevent tissue damage [4]. The myeloid differentiation primary response gene 88(MyD88) signaling pathway has been implicated in perpetuating the inflammatory response in experimental peritonitis and colitis. This pathway is shared by the TLRs except
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