In gout, monosodium urate (MSU) crystals deposited in the joint stimulate both acute neutrophilic inflammation and chronic synovitis that may lead to bone and cartilage destruction. MSU crystals trigger inflammation in large part via their capacity to directly activate cells, including synovial lining cells and phagocytes. However, the precise molecular identity of the cell recognition factors for inert MSU crystals to induce gouty inflammation has remained unclear. We recently discovered that the innate immune pattern recognition receptors (PRRs) plasma membrane TLR2, TLR4, and their common intracellular adapter protein MyD88 mediate cellular recognition of inert, endotoxin-free preparations of MSU crystals in vitro, and determine the inflammatory potential of MSU crystals in vivo. In addition, we observed that another PRR CD14, the TLR2 and TLR4 accessory molecule, directly binds MSU crystals in vitro, and mediates MSU crystal-induced inflammatory responses in vivo. Moreover, we now observe that cryopyrin/NALPS, an intracellular PRR, also plays an important role in promoting MSU crystal-induced inflammation in vivo. Thus, the central objective of this study is to test the hypothesis that the bridging of specific extracellular (CD14, TLR2, and TLR4) and intracellular (cryopyrin/NALP3) innate immune PRRs coordinately transduce and link extracellular engagement and uptake to intracellular responses to MSU crystals, which are central to gouty inflammation. To do so, we will test the hypothesis in two aims.
In aim 1, we will test the hypothesis that extracellular engagement of MSU crystals by CD14, TLR2, and TLR4 is essential for MSU crystal-induced inflammatory responses in phagocytes.
In Aim 2, we will test the hypothesis that two distinct intracellular innate immune mechanisms govern inflammatory responses induced by MSU crystals: (1) canonical TLR2 and TLR4 signaling through the TLR adapter protein MyD88 leads to expression of NF-kappaB regulated inflammatory cytokines. (2) MyD88-independent intracellular engagement of the cryopyrin/NALPS inflammasome pathway dependent on internalized (MSU crystal-bound) CD14, TLR2 or TLR4 mediates IL-1beta maturation and seretion. Completion of this work will help further understanding the mechanisms of acute gouty inflammation, how to control gouty arthritis and potentially other forms of crystal-induced inflammation. ? ? ?
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