FcγR mediates TLR2- and Syk-dependent NLRP3 inflammasome activation by inactivated Francisella tularensis LVS immune complexes

Journal of Leukocyte Biology

Jonathan A. Harton¹  Ellen B. Duffy¹  Danielle Hunt¹  James R. Drake¹  Sivakumar Periasamy¹ 

[1] Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USADepartment of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USADepartment of Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA

关键词: macrophage;    IL-1β;    vaccine;   

DOI  :  10.1189/jlb.2A1215-555RR

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

IgG (mAb)-opsonized, inactivated Francisella tularensis LVS (iFt-mAb) enhances TLR2-dependent IL-6 production by macrophages via Fcγ receptors (FcγR). In mice, vaccination with iFt-mAb provides IgA-dependent protection against lethal challenge with Ft LVS. Because inflammasome maturation of IL-1β is thought important for antibody-mediated immunity, we considered the possibility that iFt-mAb elicits an FcγR-dependent myeloid cell inflammasome response. Herein, we find that iFt-mAb enhances macrophage and dendritic cell IL-1β responses in a TLR2- and FcγR-dependent fashion. Although iFt-mAb complexes bind FcγR and are internalized, sensing of cytosolic DNA by absent in melanoma 2 (AIM2) is not required for the IL-1β response. In contrast, ASC, caspase-1, and NLR family pyrin domain-containing 3 (NLRP3) are indispensable. Further, FcγR-mediated spleen tyrosine kinase (Syk) signaling is required for this NLRP3-dependent IL-1β response, but the alternative IL-1β convertase caspase-8 is insufficient. Finally, iFt-mAb-vaccinated wild-type mice exhibit a significant delay in time to death, but IL-1R1– or Nlrp3-deficient mice vaccinated in this way are not protected and lack appreciable Francisella-specific antibodies. This study demonstrates that FcγR-mediated Syk activation leads to NLRP3 inflammasome-dependent IL-1β production in macrophages and suggests that an Nlrp3- and IL-1R–dependent process contributes to the IgA response important for protection against Ft LVS. These findings extend our understanding of cellular responses to inactivated pathogen-opsonized vaccine, establish FcγR-elicited Syk kinase-mediated NLRP3 inflammasome activation, and provide additional insight toward understanding crosstalk between TLR and FcγR signals.

【 授权许可】

Unknown