title: Inflammasome-Independent NLRP3 Restriction of a Protective Early Neutrophil Response to Pulmonary Tularemia.
abstract: Francisella tularensis (Ft) causes a frequently fatal, acute necrotic pneumonia in humans and animals. Following lethal Ft infection in mice, infiltration of the lungs by predominantly immature myeloid cells and subsequent myeloid cell death drive pathogenesis and host mortality. However, following sub-lethal Ft challenge, more mature myeloid cells are elicited and are protective. In addition, inflammasome-dependent IL-1β and IL-18 are important for protection. As Nlrp3 appears dispensable for resistance to infection with Francisella novicida, we considered its role during infection with the virulent Type A strain SchuS4 and the attenuated Type B live vaccine strain LVS. Here we show that both in vitro macrophage and in vivo IL-1β and IL-18 responses to Ft LVS and SchuS4 involve both the Aim2 and Nlrp3 inflammasomes. However, following lethal infection with Francisella, IL-1r-, Caspase-1/11-, Asc- and Aim2-deficient mice exhibited increased susceptibility as expected, while Nlrp3-deficient mice were more resistant. Despite reduced levels of IL-1β and IL-18, in the absence of Nlrp3, Ft infected mice have dramatically reduced lung pathology, diminished recruitment and death of immature myeloid cells, and reduced bacterial burden in comparison to wildtype and inflammasome-deficient mice. Further, increased numbers of mature neutrophil appear in the lung early during lethal Ft infection in Nlrp3-deficient mice. Finally, Ft infection induces myeloid and lung stromal cell death that in part requires Nlrp3, is necrotic/necroptotic in nature, and drives host mortality. Thus, Nlrp3 mediates an inflammasome-independent process that restricts the appearance of protective mature neutrophils and promotes lethal necrotic lung pathology.
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Periasamy
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Hongnga T
authors.identifier: http://orcid.org/0000-0002-9923-7846
authors.initials: HT
authors.lastname: Le
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Ellen B
authors.initials: EB
authors.lastname: Duffy
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Heather
authors.identifier: http://orcid.org/0000-0003-2895-014X
authors.initials: H
authors.lastname: Chin
authors.affiliation: Department of Immunology and Microbial Disease, Albany Medical College, Albany, New York, United States of America.
authors.forename: Jonathan A
authors.identifier: http://orcid.org/0000-0002-0350-1877
authors.initials: JA
authors.lastname: Harton
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005604:Francisella tularensis / Q000276:immunology; D007150:Immunohistochemistry; D016130:Immunophenotyping; D058847:Inflammasomes; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology*; D014406:Tularemia / Q000276:immunology*
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse