disintegrin and metalloproteinase with thrombospondin motifs [45]. These findings reinforce our observations that the neutral- ization of S100A9 and calprotectin preserves joint integrity in arthritis. Indeed, we observed little or no bone erosion and cartilage destruction in groups treated with anti-S100A9 Abs. These observations are consistent with decreased infiltration of neutrophils and monocytes, which are known to secrete matrix- modifying enzymes involved in joint degradation. S100A9 may have a direct role in the release of MMPs. Indeed, we previously showed that stimulation of neutrophils with S100A9 induces the degranulation of secretory and specific/gelatinase granules con- taining MMP9 or collagenase [46]. Based on present and previous studies, we propose a model linking S100A9 and calprotectin in the development of acute RA and the exacerbation of inflammation in the synovium. Briefly, innate immune cells, such as monocytes and neutrophils, are first activated by inflammatory stimuli, triggering the release of S100A9 and calprotectin. These DAMPs can act in either an autocrine or paracrine manner to favor cell migration towards the site of inflammation. Once in the synovium, infiltrated cells release pro-inflammatory mediators that subsequently activate resident immune and non-immune cells, resulting in a feed-forward loop of inflammation that ultimately causes tissue destruction. Numerous DAMPs including S100A9 and calprotectin are among the pro- inflammatory factors liberated by activated resident cells. Indeed, the genes encoding S100A8 and S100A9 are induced in various cell types in response to inflammatory agonists like epithelial and endothelial cells, keratinocytes, fibroblasts and macrophages [47,48]. The local presence of S100A9 and calprotectin in the References 1. Marinova-Mutafchieva L, Williams RO, Mason LJ, Mauri C, Feldmann M, et al. 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