Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome
Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W.
American Society of Hematology (ASH)
Published 2018
American Society of Hematology (ASH)
Published 2018
| Publication Date: |
2018-03-30
|
|---|---|
| Publisher: |
American Society of Hematology (ASH)
|
| Print ISSN: |
0006-4971
|
| Electronic ISSN: |
1528-0020
|
| Topics: |
Biology
Medicine
|
| Keywords: |
Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis, Clinical Trials and Observations
|
| Published by: |
| _version_ | 1836398870292070400 |
|---|---|
| autor | Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W. |
| beschreibung | Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4 T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4 T337S -induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4 T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-–induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b , Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4 T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18–driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS. |
| citation_standardnr | 6221349 |
| datenlieferant | ipn_articles |
| feed_id | 310 |
| feed_publisher | American Society of Hematology (ASH) |
| feed_publisher_url | http://www.hematology.org/ |
| insertion_date | 2018-03-30 |
| journaleissn | 1528-0020 |
| journalissn | 0006-4971 |
| publikationsjahr_anzeige | 2018 |
| publikationsjahr_facette | 2018 |
| publikationsjahr_intervall | 7984:2015-2019 |
| publikationsjahr_sort | 2018 |
| publisher | American Society of Hematology (ASH) |
| quelle | Blood |
| relation | http://www.bloodjournal.org/cgi/content/short/131/13/1442?rss=1 |
| schlagwort | Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis, Clinical Trials and Observations |
| search_space | articles |
| shingle_author_1 | Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W. |
| shingle_author_2 | Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W. |
| shingle_author_3 | Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W. |
| shingle_author_4 | Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W. |
| shingle_catch_all_1 | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis, Clinical Trials and Observations Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4 T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4 T337S -induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4 T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-–induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b , Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4 T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18–driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS. Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_catch_all_2 | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis, Clinical Trials and Observations Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4 T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4 T337S -induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4 T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-–induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b , Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4 T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18–driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS. Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_catch_all_3 | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis, Clinical Trials and Observations Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4 T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4 T337S -induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4 T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-–induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b , Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4 T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18–driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS. Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_catch_all_4 | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis, Clinical Trials and Observations Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4 T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4 T337S -induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4 T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-–induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b , Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4 T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18–driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS. Weiss, E. S., Girard-Guyonvarch, C., Holzinger, D., de Jesus, A. A., Tariq, Z., Picarsic, J., Schiffrin, E. J., Foell, D., Grom, A. A., Ammann, S., Ehl, S., Hoshino, T., Goldbach-Mansky, R., Gabay, C., Canna, S. W. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_title_1 | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome |
| shingle_title_2 | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome |
| shingle_title_3 | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome |
| shingle_title_4 | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome |
| timestamp | 2025-06-30T23:33:57.072Z |
| titel | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome |
| titel_suche | Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome |
| topic | W WW-YZ |
| uid | ipn_articles_6221349 |