The pulmonary antimicrobial immune defense is mediated by the cooperation of multiple cell types including airway epithelial cells (AECs) and professional immune cells. However, mechanisms underlying pulmonary immune regulation are not fully uncovered. Here we show that Regnase-1, an RNase critical for suppressing activation of immune cells by degrading inflammatory mRNAs, is expressed in AECs and plays pivotal roles in orchestrating pulmonary surface barrier function and immune responses against Pseudomonas aeruginosa. Regnase-1 in the lung is rapidly degraded upon exposure with P. aeruginosa or the stimulation of TLR. To investigate the influence of Regnase-1 disappearance from the lung, we analyzed the lung of Regnase-1–/– mice, and we found the overt accumulation of neutrophils and 15-fold increase of bronchoalveolar lavage fluid IgA concentration in Regnase-1–/– mice compared with wild-type mice. These phenotypes were largely attenuated in mice lacking Regnase-1 only in radiosensitive cells, suggesting the vital role of Regnase-1 in the AECs. RNA-sequencing revealed that the loss of Regnase-1 in AECs enhanced the expression of newly identified Regnase-1 target genes involved in direct exclusion of pathogens (Muc5b, Sftpd, Ltf), neutrophil recruitment (Cxcl1, Cxcl5), Th17 recruitment (Cxl20), and transportation of IgA in AECs (Pigr), as well as the attraction of IgA producing plasma cells (Ccl28). Indeed, mice lacking Regnase-1 specifically in AECs showed the enhancement of natural and adaptive immunity through the induction of neutrophils, Th17 cells, and IgA producing plasma cells. Concordantly, these mice showed the reinforcement of neutrophilc inflammation and antigen-specific IgA secretion in the course of P. aeruginosa airway infection in vivo, conferring the resistance through the accelerated elimination of the pathogen. These results demonstrate that Regnase-1 degradation in pathogen-sensing AECs is the key mechanism for the activation of anti-bacterial immunity.