# ADAM8 in macrophages exacerbates sepsis-induced cardiomyopathy by impeding efferocytosis

## TL;DR

This study shows that ADAM8 in macrophages worsens heart damage during sepsis by reducing the cells' ability to clear dead tissue, suggesting ADAM8 could be a new target for treatment.

## Contribution

The study reveals a novel role for ADAM8 in sepsis-induced cardiomyopathy by linking it to impaired macrophage efferocytosis and cardiac dysfunction.

## Key findings

- Macrophage-specific ADAM8 knockout improved heart function and survival in sepsis models.
- ADAM8 deficiency enhanced efferocytosis by increasing MerTK and reducing soluble Mer.
- Administering soluble Mer reversed the protective effects of ADAM8 knockout in septic mice.

## Abstract

Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication characterized by acute cardiac dysfunction during sepsis., and macrophages play a crucial role in SICM pathogenesis. ADAM8 has been implicated in inflammation-driven diseases, yet its role in SICM remains uncharted.

Mouse models of SICM were established using lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Macrophage-specific ADAM8 knockout (CKO) mice were generated. RNA transcriptome sequencing was conducted on left ventricular tissues sourced from ADAM8 CKO mice, as well as on RAW264.7 cell lines that were treated with both ADAM8 knockdown (KD) lentivirus and LPS.

Here, we demonstrate that ADAM8 expression is significantly upregulated in cardiac macrophages of SICM mice using single-cell transcriptomics and immunofluorescence. Macrophage-specific ADAM8 CKO mice exhibited preserved cardiac function, reduced myocardial injury markers, attenuated apoptosis (decreased Bax/Bcl2 ratio), and enhanced survival in both LPS-induced and CLP sepsis models. Transcriptomic analysis revealed downregulation of cytokine-cytokine receptor pathways in CKO hearts, suggesting diminished inflammatory responses. Mechanistically, ADAM8 deficiency promoted macrophage efferocytosis by increasing phagocytic receptors (MerTK) while reducing soluble Mer (sMer) generation. Conversely, sMer administration abolished the cardioprotective effects in CKO mice, exacerbating cardiac dysfunction and mortality.

Our findings identify ADAM8 as a critical regulator of macrophage-mediated inflammation and impaired macrophage efferocytosis in SICM. Targeting ADAM8 or its downstream effectors may represent a novel therapeutic strategy for sepsis-induced cardiac complications.