CCL 28 modulates neutrophil responses during infection with mucosal pathogens 1

32 The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not 33 well understood. Here we show that CCL28 promotes neutrophil accumulation to the gut of mice 34 infected with Salmonella and to the lung of mice infected with Acinetobacter. Neutrophils isolated 35 from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, 36 on their surface. The functional consequences of CCL28 deficiency were different between the 37 two infections, as Ccl28-/mice were highly susceptible to Salmonella gut infection, but highly 38 resistant to otherwise lethal Acinetobacter lung infection. In vitro, unstimulated neutrophils 39 harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following 40 phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil 41 antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, 42 all processes that were largely dependent on CCR3. Consistent with the different outcomes in the 43 two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not 44 of Acinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens 45 by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but 46 also exacerbate disease depending on the mucosal site and the infectious agent. 47