Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis

The macrophage response to infected microbes is crucial for the development of life-threatening sepsis. However, the mechanisms underlying pathophysiological regulation of macrophage subsets during sepsis remain poorly understood. Here, we report a novel mechanism in which the adhesion and degranulation-promoting adapter protein (ADAP) is essential for priming macrophages to induce podoplanin (PDPN) in response to bacterial infection during sepsis. We showed that ADAP expression was robustly induced in macrophages following LPS stimulation and was associated with sepsis severity. Furthermore, PDPN failed to be upregulated in TLR4 stimulated macrophages deficient in ADAP. A distinct PDPNhi peritoneal macrophage (PM) subset, which exhibited an M2-like phenotype and enhanced phagocytic activity, was generated in WT but not in ADAP-deficient septic mice. The blockade of PDPNhi PMs mimicked the effect of ADAP deficiency, which exacerbated sepsis. Mechanistically, BTK-mediated ADAP Y571 phosphorylation worked together with mTOR to converge on STAT3 activation for the transactivation of the PDPN promoter. Moreover, agonist activation of STAT3 profoundly potentiated the PDPNhi PM subset generation and alleviated sepsis severity in mice. Together, our findings reveal a novel mechanism whereby ADAP resets macrophage function by controlling the TLR4-induced upregulation of PDPN as a host innate immune defense during sepsis.