Editors' ChoiceInnate Immunity

Limiting the Damage

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Science's STKE  20 Sep 2005:
Vol. 2005, Issue 302, pp. tw336
DOI: 10.1126/stke.3022005tw336

Toll-like receptors (TLR), found in cells of the innate immune system, recognize conserved microbial patterns to mediate proinflammatory responses and thereby eliminate pathogens. When out of control, however, these responses can be dangerous to the host; indeed, activation of TLR4 by lipopolysaccharide (LPS, found in Gram-negative bacterial membranes) can lead to life-threatening endotoxic shock. Tissue damage can lead to the release of adenosine triphosphate (ATP); thus, Kaufmann et al. investigated the possible role of extracellular ATP as a "damage signal" that modulates TLR signaling. The authors used reverse transcription polymerase chain reaction (RT-PCR) to show that human peripheral blood monocytes expressed various P2Y and P2X purinergic receptors. Exposure to ATP increased monocyte adenosine 3′,5′-monophosphate (cAMP) content, elicited a biphasic intracellular calcium signal, stimulated pseudopodial retraction, and promoted nondirectional cell migration. LPS stimulated the production of tumor necrosis factor α (TNFα); ATPγS inhibited LPS-stimulated secretion of TNFα and monocyte chemoattractant protein-1 (MCP-1), whereas it enhanced LPS-stimulated secretion of the anti-inflammatory interleukin-10 (IL-10). Pharmacological analysis indicated that this likely involved stimulation of the cAMP signaling pathway, mediated through P2Y11. Similarly, ATPγS inhibited the production of TNFα and MCP-1, and enhanced that of IL-10, elicited by stimulating TLR2 or the TLR2/6 complex with the appropriate ligands. Thus, the authors suggest that ATP released from injured cells acts through P2Y11 and the cAMP pathway to limit the proinflammatory response to TLR activation.

A. Kaufmann, B. Musset, S. H. Limberg, V. Renigunta, R. Sus, A. H. Dalpke, K. M. Heeg, B. Robaye, P. J. Hanley, "Host tissue damage" signal ATP promotes non-directional migration and negatively regulates Toll-like receptor signaling in human monocytes. J. Biol. Chem. 280, 32459-32467 (2005). [Abstract] [Full Text]