ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis
Sarang Tartey, … , Amanda Burton, Thirumala-Devi Kanneganti
Sarang Tartey, … , Amanda Burton, Thirumala-Devi Kanneganti
Published April 9, 2018
Citation Information: J Clin Invest. 2018;128(5):2042-2047. https://doi.org/10.1172/JCI98446.
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Concise Communication Immunology

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

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.

Authors

Sarang Tartey, Prajwal Gurung, Tejasvi Krishna Dasari, Amanda Burton, Thirumala-Devi Kanneganti

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Figure 3

ASK1/2 instigates Ptpn6spin-mediated disease by promoting proinflammatory signaling.

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ASK1/2 instigates Ptpn6spin-mediated disease by promoting proinflammator...
(A) Serum was harvested from Ptpn6+/– (n = 7), Ptpn6spin (n = 12), and Ptpn6spinAsk1–/–Ask2–/– (n = 9) mice and the concentrations of cytokines (G-CSF, IL-6) and chemokines (KC/CXCL-1, MCP-1) were measured by ELISA. (B) Footpads from Ptpn6+/–, Ptpn6spin, and Ptpn6spinAsk1–/–Ask2–/– mice were homogenized and the concentrations of cytokines (G-CSF, IL-6) and chemokines (KC/CXCL-1, MCP-1) were measured by ELISA in the quantified lysates. All data are mean ± SEM. Each point represents an individual mouse, and the line represents mean ± SEM. (C) Neutrophils from bone marrow were stimulated with recombinant mouse IL-1α (10 ng/ml) for the indicated time period. Whole-cell lysates were prepared and expression of p-IκBα, IκBα, p-ERK1/2, ERK1/2, p-p38, and p38 was determined by Western blotting. (D) Footpad lysates were prepared and expression of p-IκBα, IκBα, p-ERK1/2, ERK1/2, p-p38, and p38 was determined by Western blotting. β-Actin was used as an internal control. Results are representative of 3 independent experiments. (A and B) Two-way ANOVA was used to determine the significance between the 2 groups analyzed. NS, not significant. *P < 0.05, ***P < 0.001, ****P < 0.0001.