In response to injury, epithelial cells recruit inflammatory cells and somehow manage to confine them to a restricted area. How this occurs is now clearer, following a report by Li et al. in Cell that provides evidence that the proteinase matrilysin (which is also known as matrix metalloproteinase 7), the proteoglycan syndecan 1 and the chemokine KC act in concert to direct inflammatory cells to sites of injury in the lung.

Having observed increased matrilysin expression in lung alveolar epithelial cells in a bleomycin-induced mouse model of lung fibrosis, the authors used matrilysin-null (MAT−/−) mice to assess the role of matrilysin in injury. MAT−/− mice showed less extensive alveolar fibrosis and were protected against bleomycin-induced lethality compared with wild-type animals. The authors consistently saw less neutrophils in the lumen of MAT−/− lung alveoli — they all remained in the interstitial perivascular space.

So, matrilysin might be regulating the activity of a neutrophil chemotactic factor derived from epithelial cells; neutrophils, macrophages and interstitial cells don't express matrilysin. A candidate chemoattractant was KC, which the authors indeed found to be low (at the protein level) in MAT−/− broncho-alveolar lavage (BAL) but to accumulate in the lung tissue overall, compared with wild-type mice.

The indication, then, was that matrilysin somehow affects the movement of KC into the lumen. But KC isn't a direct matrilysin substrate, so what was the intermediate? On the basis of published information, syndecans were likely suspects — and syndecan 1 is also expressed in lung epithelial cells. In response to bleomycin, a marked increase in soluble syndecan 1 in BAL, but reduced staining for syndecan 1 in alveoli, occurred in wild-type animals. No such change occurred in MAT−/− mice. Cell-culture studies showed that matrilysin can cleave syndecan, and immunoprecipitation experiments then showed that KC binds to the ectodomain of syndecan 1 in BAL of wild-type mice. Further experiments, using bleomycin-treated syndecan 1 null mice, indicated that syndecan 1 was needed to mobilize KC.

An attractive model is that injury induces epithelial cells to synthesize, secrete and deposit KC onto syndecan 1. Matrilysin then cleaves this, freeing the syndecan ectodomain–KC complex, which entices neutrophils to the alveolar space.