CCL28 modulates neutrophil responses and impacts the trajectory of mucosal infections

Perez-Lopez, Araceli; Silva, Steven; Dillon, Nicholas; Brandt, Stephanie L.; Gerner, Romana R.; Lee, Michael H.; Melchior, Karine; Torres-Ruiz, Jiram; Sosa-Hernandez, Victor A.; Cervantes-Diaz, Rodrigo; Perez-Fragoso, Alfredo; Romero-Ramirez, Sandra; Gomez-Martin, Diana; Maravillas-Montero, Jose L.; Nuccio, Sean-Paul; Nizet, Victor; Raffatellu, Manuela

The mucosal chemokine CCL28 is highly upregulated during infection but its role in this context is not well understood. Utilizing Ccl28-/- mice, we discovered that CCL28 promotes neutrophil recruitment to the infected mucosa. Neutrophils from these tissues expressed the CCL28 receptor CCR3, and CCR3 stimulation enhanced neutrophil antimicrobial activity against Salmonella. Moreover, bone marrow neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. The functional consequences of CCL28 deficiency were strikingly different between two infection models, as Ccl28-/- mice were highly susceptible to Salmonella gut infection, but highly resistant to otherwise lethal Acinetobacter lung infection. CCL28 thus plays a critical role in the immune response to mucosal pathogens by regulating neutrophil recruitment and activation, a response whose ultimate consequence ranges from beneficial (control of the pathogen) to exceedingly negative (death of the host), depending on the infectious agent and impacted organs.