Inflammation NO Switch in Lung Inflammation

L. Bryan Ray

Science, Science Signaling, AAAS, Washington, DC 20005, USA

The secreted protein surfactant protein D (SP-D) serves a protective function in the lung, binding to invading microorganisms to initiate immune defense responses. But its actions are more complicated than that. The protein also binds to other signaling proteins, like the receptor complex of CD91 and calreticulin, or to signal inhibitory regulatory protein (SIRP ), thereby activating the tyrosine phosphatase SHP-1. The former appears to be a pro-inflammatory stimulus mediated by the tail domain of the protein, whereas the latter is anti-inflammatory and appears to depend on the head domain. Guo et al. now provide evidence that propensity of SP-D to promote one or the other of these opposing effects is strongly influenced by S-nitrosylation of two cysteine residues in the hydrophobic tail region of the protein. Mutagenesis studies identified two cysteine residues that were required for S-nitrosylation and showed that the S-nitrosylated protein dissociated from the usual large multimers into trimers. In an in vivo model of lung inflammation in rats and mice, the authors showed evidence of S-nitrosylation of SP-D when inflammation was induced, and this effect was lost in mice lacking the nitric oxide–producing enzyme iNOS. Although effects of S-nitrosylation could partly result from dissociation of the multimeric state in which the tail domains are buried and cannot interact with other proteins, S-nitrosylation also appears to have other effects, because cysteine mutants that also caused dissociation did not have equivalent effects on stimulation of chemotaxis of cultured macrophages. The results may aid in understanding the complicated roles of NO in the lung, where it is necessary for helpful functions like airway dilation and immune responses but can also contribute to pathological events like acute lung injury or asthma.

C.-J. Guo, E. N. Atochina-Vasserman, E. Abramova, J. P. Foley, A. Zaman, E. Crouch, M. F. Beers, R. C. Savani, A. J. Gow, S-Nitrosylation of surfactant protein-D controls inflammatory function. PLoS Biol. 6, e266 (2008). [Online Journal]