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ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2018 May 01; Vol. 128 (5), pp. 2042-2047. Date of Electronic Publication: 2018 Apr 09. - Publication Year :
- 2018
-
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 Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin 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 Ptpn6spin 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 Ptpn6spin mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in Ptpn6spin mice. Mechanistically, ASK regulates Ptpn6spin-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.
- Subjects :
- Animals
Disease Models, Animal
Inflammation enzymology
Inflammation genetics
Inflammation immunology
Inflammation pathology
MAP Kinase Kinase Kinase 5 genetics
MAP Kinase Kinase Kinase 5 metabolism
MAP Kinase Kinase Kinases genetics
MAP Kinase Kinase Kinases metabolism
Mice
Mice, Knockout
Neutrophils enzymology
Neutrophils pathology
Protein Tyrosine Phosphatase, Non-Receptor Type 6 genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 6 immunology
Signal Transduction genetics
Sweet Syndrome enzymology
Sweet Syndrome genetics
Sweet Syndrome pathology
MAP Kinase Kinase Kinase 5 immunology
MAP Kinase Kinase Kinases immunology
Neutrophil Infiltration
Neutrophils immunology
Signal Transduction immunology
Sweet Syndrome immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 128
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 29629899
- Full Text :
- https://doi.org/10.1172/JCI98446