Myeloid CD38 deficiency ameliorates sepsis-induced cardiomyopathy by alleviating inflammatory response through the SIRT1/NF-κB/NLRP3 pathways.

BACKGROUND

Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication with limited therapeutic options. Macrophage-driven inflammation and pyroptosis are central to SICM pathogenesis, but the role of myeloid CD38, the primary NAD+ hydrolase, in SIC remains unexplored.

METHODS

Myeloid-specific CD38 knockout (CD38ᴹᴷᴼ) mice and CD38ᶠˡ°ˣ controls were subjected to cecal ligation and puncture (CLP) to induce sepsis. Cardiac function, myocardial inflammation, pyroptosis, and oxidative stress were assessed. Bone marrow-derived macrophages (BMDMs) and conditioned medium studies were used to investigate mechanisms and paracrine effects on cardiomyocytes.

RESULTS

CD38 was upregulated in cardiac macrophages of septic mice. Myeloid CD38 deletion improved cardiac function, reduced injury markers, and attenuated myocardial inflammation, pyroptosis, and oxidative stress. CD38ᴹᴷᴼ mice exhibited reduced M1 and enhanced M2 macrophage polarization. CD38-deficient BMDMs showed suppressed NF-κB activation, NLRP3 inflammasome assembly, and glycolysis-related gene expression (HIF1α, SLC2A1), with concomitant NAD+ accumulation and SIRT1 upregulation. SIRT1 inhibition reversed these protective effects. Conditioned medium from CD38ᴹᴷᴼ macrophages protected cardiomyocytes from oxidative injury. Proteomic analysis revealed enrichment of mitochondrial proteins in the CD38-deficient macrophage secretome.

CONCLUSIONS

Myeloid CD38 deficiency protects against SIC by activating the SIRT1/NF-κB/NLRP3 axis, promoting M2 polarization, suppressing pyroptosis, and remodeling the macrophage secretome. Targeting myeloid CD38 represents a promising therapeutic strategy for SICM.