Integrin Integral to Innate Immunity

Science Signaling  28 Jul 2009:
Vol. 2, Issue 81, pp. ec250
DOI: 10.1126/scisignal.281ec250

The innate immune system uses a range of receptors to detect invading bacteria or viruses, the latter often being detected through recognition of viral DNA or RNA inside a host cell. Di Paolo et al. now propose another mechanism in which a viral protein is detected by integrins on the cell surface of macrophages. The authors found that proinflammatory gene expression was activated in macrophages within 10 min of injection of mice with adenovirus. Experiments with knockout animals showed that the immune response to adenovirus was dependent on production of the inflammatory cytokine interleukin-1α. Although the NLRP inflammasome is thought to recognize adenoviral dsDNA, Di Paolo found that mice lacking NLRP-3 or another nucleic acid detector, Toll-like receptor 9, still responded well to the adenovirus. The key appeared to be interaction of RGD (arginine-glycine-aspartic acid) motifs in a particular viral protein with integrins on the cell surface, an interaction that helps the virus gain internalization into the cell. Mice lacking integrin β3 (but not integrin β1) showed reduced expression of IL-1α mRNA, and a mutant virus in which the RGD motif in the viral protein that interacts with the receptor was mutated also reduced the transcriptional response in macrophages. The authors suggest that such rapid detection of virus by integrins on the cell surface and early initiation of the cellular response may be even more beneficial than detection of viral RNA or DNA inside the cell. Fitzgerald points out in commentary that the results are made especially pertinent by the fact that the potential for use of adenoviruses in gene therapy is hampered by their initiation of inflammatory responses in the host.

N. C. Di Paolo, E. A. Miao, Y. Iwakura, K. Murali-Krishna, A. Aderem, R. A. Flavell, T. Papayannopoulou, D. M. Shayakhmetov, Virus binding to a plasma membrane receptor triggers interleukin-1α-mediated proinflammatory macrophage response in vivo. Immunity 31, 110–121 (2009).[PubMed]

K. A. Fitzgerald, Integr-ating IL-1α in antiviral host defenses. Immunity 31, 7–9 (2009).[PubMed]