Sepsis Subtypes in Blood and Liver Define Precision Strategy for CXCR2 Blockade

Sepsis is classified into distinct transcriptomic endotypes. Yet specific cellular drivers for those subtypes remain ambiguous. Although dysregulated CXCL8-CXCR1/2 signaling and neutrophil hyperactivation are implicated in severe endotypes, the therapeutic window and organ-specific consequences of CXCR2 antagonism remain unclear. To determine whether murine transcriptomic subtypes (MTSs) recapitulate human consensus transcriptomic subtypes (CTSs) and evaluate how subtype state dictates the efficacy and trade-offs of Danirixin in polymicrobial sepsis. We reanalyzed septic patients whole-blood CITE-seq data to characterize CXCL8- CXCR2 signaling. Using a severity-stratified murine polymicrobial model, we evaluated Danirixins efficacy. Endpoints included 7-day survival, cytokine profiling, and hepatic histology. Early (24-h) multi-compartment assessments of bacterial burden, NETosis, immune infiltration, and paired blood-liver bulk RNA sequencing informed MTS classification and mechanistic insights. Human CTS1 exhibited neutrophil and progenitor expansion, elevated CXCL8/CD11b expression, and reduced CXCR2, defining a hyperactivated, dysregulated myeloid state. Applying CTS-derived gene signatures to murine tissues identified three MTSs correlating with pathogen load and interleukin-6. Human CTS1 dysregulation was mirrored in murine MTS3. Crucially, Danirixin improved 7-day survival in MTS3 sepsis. Conversely, in MTS1, Danirixin attenuated systemic NETosis and hepatic injury but exacerbated bacterial dissemination, without improving survival. Murine transcriptomic subtypes translationally model human sepsis subtypes. In severely dysregulated host-response states (MTS3/CTS1), CXCR2 antagonism effectively mitigates maladaptive, neutrophil-driven immunopathology. However, in less severe subtypes, it compromises early bacterial containment. These findings therefore support for endotype-guided precision targeting of CXCR2 in sepsis. One Sentence SummaryTargeting CXCR2 improves sepsis survival only in a specific molecular subtype, showing that host traits dictate therapeutic outcomes.