Progranulin Plays a Central Role in Host Defense during Sepsis by Promoting Macrophage Recruitment.

RATIONALE: Progranulin, a widely expressed protein, has multiple physiological functions. The functional role of progranulin in the host response to sepsis remains unknown. OBJECTIVES: To assess the role of progranulin in the host response to sepsis. METHODS: Effects of progranulin on host response to sepsis were determined. MEASUREMENTS AND MAIN RESULTS: Progranulin concentrations were significantly elevated in adult (n = 74) and pediatric (n = 26) patients with sepsis relative to corresponding healthy adult (n = 36) and pediatric (n = 17) control subjects, respectively. By using a low-lethality model of nonsevere sepsis, we observed that progranulin deficiency not only increased mortality but also decreased bacterial clearance during sepsis. The decreased host defense to sepsis in progranulin-deficient mice was associated with reduced macrophage recruitment, with correspondingly impaired chemokine CC receptor ligand 2 (CCL2) production in peritoneal lavages during the early phase of sepsis. Progranulin derived from hematopoietic cells contributed to host defense in sepsis. Therapeutic administration of recombinant progranulin not only rescued impaired host defense in progranulin-deficient mice after nonsevere sepsis but also protected wild-type mice against a high-lethality model of severe sepsis. Progranulin-mediated protection against sepsis was closely linked to improved peritoneal macrophage recruitment. In addition, CCL2 treatment of progranulin-deficient mice improved survival and decreased peritoneal bacterial loads during sepsis, at least in part through promotion of peritoneal macrophage recruitment. CONCLUSIONS: This proof-of-concept study supports a central role of progranulin-dependent macrophage recruitment in host defense to sepsis, opening new opportunities to host-directed therapeutic strategy that manipulate host immune response in the treatment of sepsis.

Activation of IL-27 signalling promotes development of postinfluenza pneumococcal pneumonia.

Postinfluenza pneumococcal pneumonia is a common cause of death in humans. However, the role of IL-27 in the pathogenesis of secondary pneumococcal pneumonia after influenza is unknown. We now report that influenza infection induced pulmonary IL-27 production in a type I IFN-α/ß receptor (IFNAR) signalling-dependent manner, which sensitized mice to secondary pneumococcal infection downstream of IFNAR pathway. Mice deficient in IL-27 receptor were resistant to secondary pneumococcal infection and generated more IL-17A-producing γδ T cells but not αß T cells, thereby leading to enhanced neutrophil response during the early phase of host defence. IL-27 treatment could suppress the development of IL-17A-producing γδ T cells activated by Streptococcus pneumoniae and dendritic cells. This suppressive activity of IL-27 on γδ T cells was dependent on transcription factor STAT1. Finally, neutralization of IL-27 or administration of IL-17A restored the role of γδ T cells in combating secondary pneumococcal infection. Our study defines what we believe to be a novel role of IL-27 in impairing host innate immunity against pneumococcal infection.

Pneumococcal ClpP modulates the maturation and activation of human dendritic cells: implications for pneumococcal infections.

DCs are essential for host immune response to pathogens. Pneumococcal diseases still remain to be a major global-health issue, and HSP100/ClpP is a ubiquitously present virulence determinant for Streptococcus pneumoniae. Here, we show that ClpP expression facilitates the uptake and phagocytosis of pneumococci by human DCs, and it could increase apoptosis of DCs infected with pneumococci. Furthermore, pneumococcal ClpP is required for optimal production of inflammatory cytokines and chemokines and an efficient activation of adaptive immune response in DCs. Complementary, purified rClpP protein recognizes TLR4 and functionally activates human DCs by augmenting the expression of surface molecules and the production of inflammatory cytokines and chemokines dependent on MAPKs and NF-κB signaling pathways. Besides, ClpP-treated DCs induce T cell proliferation and contribute to Th1 immune response. This study describes a novel role of ClpP in the interaction of DCs with pneumococci that could provide new insight for the progression of pneumococcal diseases and has important implications for designing pneumococcal protein vaccines.