A network approach to controlling pathogenic inflammation

Aberrant inflammation appears to be a pathogenic factor in autoimmune diseases and other noxious inflammatory conditions in which the inflammatory process is misapplied, exaggerated, recurrent or chronic. The protein molecules involved in pathogenic inflammation—disease-associated proteins (DAP)—which include chemokines, cytokines, and growth factors and their receptors, appear normal; their networks of interaction are at fault. Here we demonstrate a new approach to network regulation of inflammation based on peptide sequence motifs shared by the second extra-cellular loop (ECL2) of different chemokine receptors; previously known chemokine receptor binding sites have not involved the ECL2 loop. These motifs of 9 amino acids, which we detected by sequence alignment, manifest very low E-values compared with slightly modified sequence variations, indicating that they were not likely to have evolved by chance. To test whether this shared sequence network (SSN) might serve a regulatory function, we synthesized 9-amino acid SSN peptides from the ECL2 loops of three different chemokine receptors. We administered these peptides to rats during the induction of a model of autoimmune arthritis. Two of the peptides significantly downregulated the arthritis; one of the peptides synergized with non-specific anti-inflammatory treatment with dexamethasone. These findings suggest that the SSN peptide motif reported here is likely to have adaptive value in controlling inflammation. Moreover, detection of SSN motif peptides could provide a network-based approach to immune modulation.