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.

Background: Severe trauma rapidly reprograms peripheral myeloid cells. We hypothesised that trauma-derived transcriptional programmes may exhibit distinct patterns across Alzheimer’s disease (AD) brain pathology states; this comparison does not test whether trauma exposure alters AD mechanisms or pathology. We aimed to define a reproducible NAMPT-linked trauma-response architecture and examine its associations with AD pathology axes. Methods: Trauma-responsive programmes were defined only in GSE162806 using donor-level pseudobulk analysis, assessed for replication in GSE36809 and directional preservation across NAMPT perturbation datasets, and then projected without redefinition into the SEA-AD middle temporal gyrus atlas using donor-level programme scores. Results: NAMPT increased most strongly 4 h after trauma (log2 fold change 2.53; FDR 1.45 × 10⁻⁶). A time-adjusted 350-gene NAMPT-associated network showed partial replication in GSE36809, with 82.6% directional concordance and 227/304 mapped genes meeting the prespecified replication criterion. Cross-context analysis identified SP1 and SP2 transcriptional clusters, with directional preservation supported for SP2 but not SP1. In SEA-AD (1,178,694 nuclei; 84 donors), neither the primary ADNC analysis nor the continuous MTG-local CPS analysis survived multiplicity correction. Secondary CERAD analyses showed lower NAMPT-architecture, SP1, and SP2 scores in excitatory neurons (FDR = 0.042), and the prespecified GuHCl Aβ42-plus-pTau model showed opposing conditional associations: higher Aβ42 was associated with lower programme scores, whereas higher pTau was associated with greater programme engagement. Aβ42 × pTau interactions and Micro-PVM state analyses and cognition models were not supported after correction. Conclusions: A NAMPT-associated gene network showed partial replication across trauma cohorts, while its projection into SEA-AD yielded selected, mainly excitatory-neuron pathology associations. These findings are hypothesis-generating and do not establish conserved regulatory mechanisms across peripheral myeloid and brain cells, causal effects of trauma on AD pathology, or functional recovery capacity.