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Inflammasome recognition of influenza virus is essential for adaptive immune responses.

Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A - J. Exp. Med. (2009)

Bottom Line: Although NLRP3 was required for inflammasome activation in certain cell types, CD4 and CD8 T cell responses, as well as mucosal IgA secretion and systemic IgG responses, required ASC and caspase-1 but not NLRP3.Consequently, ASC, caspase-1, and IL-1R, but not NLRP3, were required for protective immunity against flu challenge.Furthermore, we show that caspase-1 inflammasome activation in the hematopoietic, but not stromal, compartment was required to induce protective antiviral immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
Influenza virus infection is recognized by the innate immune system through Toll like receptor (TLR) 7 and retinoic acid inducible gene I. These two recognition pathways lead to the activation of type I interferons and resistance to infection. In addition, TLR signals are required for the CD4 T cell and IgG2a, but not cytotoxic T lymphocyte, responses to influenza virus infection. In contrast, the role of NOD-like receptors (NLRs) in viral recognition and induction of adaptive immunity to influenza virus is unknown. We demonstrate that respiratory infection with influenza virus results in the activation of NLR inflammasomes in the lung. Although NLRP3 was required for inflammasome activation in certain cell types, CD4 and CD8 T cell responses, as well as mucosal IgA secretion and systemic IgG responses, required ASC and caspase-1 but not NLRP3. Consequently, ASC, caspase-1, and IL-1R, but not NLRP3, were required for protective immunity against flu challenge. Furthermore, we show that caspase-1 inflammasome activation in the hematopoietic, but not stromal, compartment was required to induce protective antiviral immunity. These results demonstrate that in addition to the TLR pathways, ASC inflammasomes play a central role in adaptive immunity to influenza virus.

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Differential requirement for NLRP3, ASC, and caspase-1 for immunoglobulin isotype responses to influenza virus. WT, NLRP3-, ASC-, caspase-1–, IL-1R–, and MyD88-deficient mice were infected intranasally with a sublethal dose (10 PFU) of A/PR8 virus. Serum and nasal swab were collected at 2 wk p.i. A/PR8-specific nasal IgA levels were measured by ELISA (A). A/PR8-specific serum antibody titers were determined by serial dilution of serum total IgG (B), IgG1 (C), IgG2c (D), IgG3 (E), and IgM (F). These figures are representative of three similar experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.001 versus WT mice.
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fig3: Differential requirement for NLRP3, ASC, and caspase-1 for immunoglobulin isotype responses to influenza virus. WT, NLRP3-, ASC-, caspase-1–, IL-1R–, and MyD88-deficient mice were infected intranasally with a sublethal dose (10 PFU) of A/PR8 virus. Serum and nasal swab were collected at 2 wk p.i. A/PR8-specific nasal IgA levels were measured by ELISA (A). A/PR8-specific serum antibody titers were determined by serial dilution of serum total IgG (B), IgG1 (C), IgG2c (D), IgG3 (E), and IgM (F). These figures are representative of three similar experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.001 versus WT mice.

Mentions: Antibody responses play a critical role in the clearance of many viral pathogens including influenza virus. Previous studies have indicated the role of MyD88 in IgG2a responses to influenza infection (26, 27). We determined the contributions of inflammasomes in this process. To this end, mice were immunized with a sublethal dose (10 PFU) of live A/PR8 virus. 2 wk p.i., influenza virion–specific nasal IgA and serum titers of IgM and IgG isotype levels were measured by serial dilution. Nasal IgA responses were found to be completely dependent on ASC, caspase-1, IL-1R, and MyD88 but not on NLRP3 (Fig. 3 A). In contrast, serum IgG1 levels were significantly elevated in MyD88-deficient mice compared with WT or other inflammasome KO groups (Fig. 3 C). A slight reduction in the IgG2c response was detected in ASC−/− and caspase-1−/− mice, which was similar to that seen in IL-1R−/− and MyD88−/− mice (Fig. 3 D). Only caspase-1−/− mice had a significant reduction in IgG3 responses but not IL-1R– or MyD88-deficient mice (Fig. 3 E), indicating that caspase-1–dependent IL-1β–, IL-18–, and IL-33 (all upstream of MyD88)–independent factors play a major role in the induction of this isotype response. In contrast, no significant differences were found in serum IgM responses (Fig. 3 F). Antibody secretion in the BM chimeric mice indicated that the requirement for caspase-1 was all attributable to its expression in the hematopoietic compartment alone (Fig. S7, available at http://www.jem.org/cgi/content/full/jem.20081667/DC1). These data indicated that at least one NLRP3-independent ASC- and caspase-1–dependent inflammasome is required for nasal IgA and, to some extent, serum IgG2c responses to influenza virus. In addition, IL-1R and MyD88, which is downstream of TLRs, IL-1R, IL-18R, and ST2, are required for the same process in vivo. In contrast, IgG3 responses appear to depend mainly on caspase-1 but not on IL-1R or MyD88, whereas MyD88 has a regulatory role for IgG1 responses.


Inflammasome recognition of influenza virus is essential for adaptive immune responses.

Ichinohe T, Lee HK, Ogura Y, Flavell R, Iwasaki A - J. Exp. Med. (2009)

Differential requirement for NLRP3, ASC, and caspase-1 for immunoglobulin isotype responses to influenza virus. WT, NLRP3-, ASC-, caspase-1–, IL-1R–, and MyD88-deficient mice were infected intranasally with a sublethal dose (10 PFU) of A/PR8 virus. Serum and nasal swab were collected at 2 wk p.i. A/PR8-specific nasal IgA levels were measured by ELISA (A). A/PR8-specific serum antibody titers were determined by serial dilution of serum total IgG (B), IgG1 (C), IgG2c (D), IgG3 (E), and IgM (F). These figures are representative of three similar experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.001 versus WT mice.
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fig3: Differential requirement for NLRP3, ASC, and caspase-1 for immunoglobulin isotype responses to influenza virus. WT, NLRP3-, ASC-, caspase-1–, IL-1R–, and MyD88-deficient mice were infected intranasally with a sublethal dose (10 PFU) of A/PR8 virus. Serum and nasal swab were collected at 2 wk p.i. A/PR8-specific nasal IgA levels were measured by ELISA (A). A/PR8-specific serum antibody titers were determined by serial dilution of serum total IgG (B), IgG1 (C), IgG2c (D), IgG3 (E), and IgM (F). These figures are representative of three similar experiments. *, P < 0.05; **, P < 0.01; and ***, P < 0.001 versus WT mice.
Mentions: Antibody responses play a critical role in the clearance of many viral pathogens including influenza virus. Previous studies have indicated the role of MyD88 in IgG2a responses to influenza infection (26, 27). We determined the contributions of inflammasomes in this process. To this end, mice were immunized with a sublethal dose (10 PFU) of live A/PR8 virus. 2 wk p.i., influenza virion–specific nasal IgA and serum titers of IgM and IgG isotype levels were measured by serial dilution. Nasal IgA responses were found to be completely dependent on ASC, caspase-1, IL-1R, and MyD88 but not on NLRP3 (Fig. 3 A). In contrast, serum IgG1 levels were significantly elevated in MyD88-deficient mice compared with WT or other inflammasome KO groups (Fig. 3 C). A slight reduction in the IgG2c response was detected in ASC−/− and caspase-1−/− mice, which was similar to that seen in IL-1R−/− and MyD88−/− mice (Fig. 3 D). Only caspase-1−/− mice had a significant reduction in IgG3 responses but not IL-1R– or MyD88-deficient mice (Fig. 3 E), indicating that caspase-1–dependent IL-1β–, IL-18–, and IL-33 (all upstream of MyD88)–independent factors play a major role in the induction of this isotype response. In contrast, no significant differences were found in serum IgM responses (Fig. 3 F). Antibody secretion in the BM chimeric mice indicated that the requirement for caspase-1 was all attributable to its expression in the hematopoietic compartment alone (Fig. S7, available at http://www.jem.org/cgi/content/full/jem.20081667/DC1). These data indicated that at least one NLRP3-independent ASC- and caspase-1–dependent inflammasome is required for nasal IgA and, to some extent, serum IgG2c responses to influenza virus. In addition, IL-1R and MyD88, which is downstream of TLRs, IL-1R, IL-18R, and ST2, are required for the same process in vivo. In contrast, IgG3 responses appear to depend mainly on caspase-1 but not on IL-1R or MyD88, whereas MyD88 has a regulatory role for IgG1 responses.

Bottom Line: Although NLRP3 was required for inflammasome activation in certain cell types, CD4 and CD8 T cell responses, as well as mucosal IgA secretion and systemic IgG responses, required ASC and caspase-1 but not NLRP3.Consequently, ASC, caspase-1, and IL-1R, but not NLRP3, were required for protective immunity against flu challenge.Furthermore, we show that caspase-1 inflammasome activation in the hematopoietic, but not stromal, compartment was required to induce protective antiviral immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
Influenza virus infection is recognized by the innate immune system through Toll like receptor (TLR) 7 and retinoic acid inducible gene I. These two recognition pathways lead to the activation of type I interferons and resistance to infection. In addition, TLR signals are required for the CD4 T cell and IgG2a, but not cytotoxic T lymphocyte, responses to influenza virus infection. In contrast, the role of NOD-like receptors (NLRs) in viral recognition and induction of adaptive immunity to influenza virus is unknown. We demonstrate that respiratory infection with influenza virus results in the activation of NLR inflammasomes in the lung. Although NLRP3 was required for inflammasome activation in certain cell types, CD4 and CD8 T cell responses, as well as mucosal IgA secretion and systemic IgG responses, required ASC and caspase-1 but not NLRP3. Consequently, ASC, caspase-1, and IL-1R, but not NLRP3, were required for protective immunity against flu challenge. Furthermore, we show that caspase-1 inflammasome activation in the hematopoietic, but not stromal, compartment was required to induce protective antiviral immunity. These results demonstrate that in addition to the TLR pathways, ASC inflammasomes play a central role in adaptive immunity to influenza virus.

Show MeSH
Related in: MedlinePlus