Taming Macrophage Inflammasomes at the Sepsis-Lung Injury Interface: Lessons from Bats

Sepsis-associated lung injury remains a major cause of respiratory failure and death, yet treatment is still largely supportive once inflammatory tissue damage is established. Macrophage inflammasomes, especially the NLRP3-ASC-caspase-1 axis, occupy a central but paradoxical position in this process. They contribute to pathogen sensing and antimicrobial defense, but excessive or poorly timed activation promotes IL-1β and IL-18 release, gasdermin D-mediated pyroptosis, extracellular ASC speck propagation, neutrophil amplification, barrier disruption, alveolar edema and acute respiratory distress syndrome. Therefore, a clinically meaningful strategy may not be to abolish inflammasome activity, but to tame it. Bats provide a natural model of this principle. Despite hosting many viruses and maintaining high metabolic activity, bats limit inflammatory execution through dampened NLRP3 responsiveness, altered DNA inflammasome sensing, restrained caspase-1/IL-1β processing and ASC2-mediated inhibition of ASC-dependent inflammasomes, while preserving antiviral readiness. These findings suggest a host-defense-preserving framework for septic lung injury. This review proposes bat-inspired design rules: raising inflammasome activation thresholds, braking ASC-dependent propagation, limiting lytic effector output, targeting inflammasome-active macrophage states instead of macrophages as a bulk population, and applying biomarker-guided timing to avoid intervention during immune paralysis. We also discuss the need to define an "inflammasome-high septic lung injury" phenotype using lung injury progression, inflammasome output markers, macrophage-state signatures and immune competence indicators. Bats do not provide a ready-made therapy, but they offer a useful biological lesson: damaging inflammatory amplification can be restrained without erasing host defense.