Calreticulin in the nasal mucus promotes neutrophil migration and pathogen clearance

The nasal cavity harbors diverse microbiota, and the nasal mucosal innate defense against microbial infiltration is crucial for respiratory infections. Both the nasal mucus covering the surface of the nasal cavity and the neutrophils beneath the nasal epithelia are the first line of innate defense against pathogens. Studying nasal mucus is challenging because of difficulties in collecting stable, high-quality samples from humans. Here, we investigated how nasal mucus cooperates with neutrophils to exert antimicrobial effects. Nasal mucus proteins, derived from nasal mucosal explants of goats, can promote neutrophil migration and increase their bactericidal activity. Calreticulin, identified from total mucus proteins, triggered ICAM-1-dependent transendothelial migration of neutrophils. Moreover, calreticulin activated the Rho GTPases of neutrophils via Toll-like receptor (TLR) 2 to promote their migration and further triggered the release of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) in a manner dependent on TLR2 and TLR4, accelerating the elimination of pathogens. In vivo studies also demonstrated that nasal inoculation with calreticulin induced neutrophil recruitment to the nasal mucosa and accelerated the clearance of Pasteurella multocida. Together, these findings highlight the synergistic interaction between nasal mucus and neutrophils as an important protective feature in the nasal mucosa.