Inflammation is an important biological response of body tissues to harmful stimuli. It is essential for the host to clear invading pathogens, cell debris and to initiate tissue regeneration. However, when deregulated, it can be deleterious to the host. Tissue damage-induced neutrophil infiltration, in the absence of bacterial infection, is documented to adversely affect the resolution of numerous diseases including ischemia, asthma, gout, cancer and others. It is of great clinical interest to interrogate the mechanism and the potential selective advantages, if any, of such deleterious response. Zebrafish has many advantages in studying inflammatory responses such as its conserved innate immune system compared to mammals, availability of large batches of embryos, and the transparency of zebrafish larvae which is ideal for intravital imaging. In this study, we show that selective inhibition of tissue damage-induced inflammation upon Pseudomonas aeruginosa (PA) infection abrogates neutrophil chemotaxis and reduces survival of infected zebrafish. Such result is achieved, at least in part, through the suppression of cytosolic phospholipase A2 (cPla2), which mechanochemically integrates tissue damage- and microbe-derived cues. Thus, tissue damage-, but not microbe-, derived signals are sufficient for triggering neutrophil responses, and are essential for protecting zebrafish against infection.