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The journal of immunology : official journal of the American Association of Immunologists v.197 no.8, 2016년, pp.3315 - 3325   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

Calpain Activity Is Essential for ATP-Driven Unconventional Vesicle-Mediated Protein Secretion and Inflammasome Activation in Human Macrophages

Välimäki, Elina (Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland ) ; Cypryk, Wojciech (Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland ) ; Virkanen, Juhani (Department of Geosciences and Geography, University of Helsinki, 00014 Helsinki, Finland ) ; Nurmi, Katariina (Division of Rheumatology, Helsinki University Hospital, Helsinki University, 00015 Helsinki, Finland ) ; Turunen, Pauli M. (and ) ; Eklund, Kari K. (Department of Physiology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland ) ; Åkerman, Karl E. (Division of Rheumatology, Helsinki University Hospital, Helsinki University, 00015 Helsinki, Finland ) ; Nyman, Tuula A. (and ) ; Matikainen, Sampsa (Department of Physiology, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland ) ;
  • 초록  

    Extracellular ATP is an endogenous danger signal that is known to activate inflammatory responses in innate immune cells, including macrophages. Activated macrophages start to secrete proteins to induce an immune response, as well as to recruit other immune cells to the site of infection and tissue damage. In this study, we characterized the secretome (i.e., the global pattern of secreted proteins) of ATP-stimulated human macrophages. We show that ATP stimulation activates robust vesicle-mediated unconventional protein secretion, including exosome release and membrane shedding, from human macrophages. Pathway analysis of the identified secreted proteins showed that calpain-related pathways were overrepresented in the secretome of ATP-stimulated cells. In accordance with this, calpains, which are calcium-dependent nonlysosomal cysteine proteases, were activated upon ATP stimulation through a P2X purinoceptor 7 receptor–dependent pathway. Functional studies demonstrated that calpain activity is essential for the P2X purinoceptor 7 receptor–mediated activation of unconventional protein secretion. Unconventional protein secretion was followed by cell necrosis and NLRP3 inflammasome–mediated secretion of the mature form of the proinflammatory cytokine IL-1β. Furthermore, ATP-driven NLRP3 inflammasome activation was also dependent on calpain activity. Interestingly, pro–IL-1β and inflammasome components ASC and caspase-1 were released by ATP-activated macrophages through a vesicle-mediated secretion pathway. In conclusion, to our knowledge, we provide the first global characterization of proteins secreted by ATP-activated human macrophages and show a pivotal role for calpains in the activation of the inflammatory response during ATP exposure.


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