Dorzolamide suppresses PKCd -TIRAP-p38 MAPK signaling axis to dampen the inflammatory response

Background: Sepsis is a syndrome due to microbial infection causing impaired multiorgan function. Its underlying cause is immune dysfunction and macrophages play an essential role. Methods: TIRAP interaction with PKCd in macrophage was studied, revealing downstream signaling by Western blot and quantitative reverse transcriptase PCR. Dorzolamide (DZD) disrupting TIRAP-PKCd interaction was identified by virtual screening and validated in vitro and in septic mice. Results: The study highlights the indispensable role of TIRAP-PKCd in p38 MAPK-activation, NF-?B- and AP-1-mediated proinflammatory cytokines expression, whereas DZD significantly attenuated the signaling. Conclusion: Targeting TIRAP-PKCd interaction by DZD is a novel therapeutic approach for treating sepsis.