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ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis.

Authors :
Tartey S
Gurung P
Dasari TK
Burton A
Kanneganti TD
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.

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