Journal article
ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis
The Journal of clinical investigation, Vol.128(5), pp.2042-2047
05/01/2018
DOI: 10.1172/JCI98446
PMCID: PMC5919885
PMID: 29629899
Abstract
Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 (SH2) domain–containing phosphatase 1 (SHP-1) (referred to as
Ptpn6
spin
mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in
Ptpn6
spin
mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for several kinases such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in
Ptpn6
spin
mice. In order to identify new kinases involved in SHP-1–mediated inflammation, we took a genetic approach and discovered apoptosis signal–regulating kinases 1 and 2 (ASK1 and ASK2) as novel kinases regulating
Ptpn6
-mediated footpad inflammation. Double deletion of ASK1 and ASK2 abrogated cutaneous inflammatory disease in
Ptpn6
spin
mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in
Ptpn6
spin
mice. Mechanistically, ASK regulates
Ptpn6
spin
-mediated disease by controlling proinflammatory signaling in the neutrophils. Collectively, the present study identifies SHP-1 and ASK signaling crosstalk as a critical regulator of IL-1α–driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.
Details
- Title: Subtitle
- ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis
- Creators
- Sarang Tartey - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USAPrajwal Gurung - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USATejasvi Krishna Dasari - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USAAmanda Burton - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USAThirumala-Devi Kanneganti - Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.128(5), pp.2042-2047
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI98446
- PMID
- 29629899
- PMCID
- PMC5919885
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- CA163507,AR056296,AI124346,; AI101935 / NIH
- Language
- English
- Date published
- 05/01/2018
- Academic Unit
- Infectious Diseases; Internal Medicine
- Record Identifier
- 9984094726902771
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