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.

Mechanism of preferential complex formation by Apoptosis Signal-regulating Kinases

“…This behaviour suggests that the SAM domains of each protein contribute markedly to the heterotypic ASK1-ASK2 complexes previously reported (4)(5)(6)(7)(8)28).…”

“…Preferential hetero-oligomerisation between the ASK1 and ASK2 SAM domains is a relatively simple molecular mechanism to explain the greater efficacy in eliciting stress responses in various settings (4)(5)(6)(7)(8). With isolated SAM domains the heterocomplex appears to be more stable at equivalent concentrations, which if translated to full-length proteins would mean that higher-order active complexes form more readily and are more persistent.…”

“…For instance, ASK1 is now well established in the response to oxidative stress and inflammatory cytokines (2,3). ASK1 and ASK2 are required for effective responses to viral infection (4)(5)(6), to prime NLR inflammasomes following challenge by bacterial infection (7), and together act to mediate neutrophillic dermatitis (8). In simplified terms, it appears that ASK1 and ASK2 in isolation are each able to promote some level of P38/JNK activation and stress response, but their concerted action generates a broader inflammatory response, and cell death.…”

Inflammasomes in the pathophysiology of autoinflammatory syndromes

“…Interestingly, disease induction in Ptpn6 spin mice is mediated by RIPK1 and IL‐1α but not by IL‐1β . Furthermore, we have shown the involvement of TAK1, ASK1/2, SYK, and caspase association and recruitment domain 9 (CARD9) signaling pathways in mediating the footpad inflammation in Ptpn6 spin mice . Because pro‐IL‐1α is fully biologically active and constitutively expressed in a wide variety of cell types, understanding IL‐1α cytokine biology, which remains significantly obscure, will shed more light on the pathogenesis of this inflammatory disorder and could provide much‐needed targeted therapy for these rare diseases.…”

“…(CARD9) signaling pathways in mediating the footpad inflammation in Ptpn6 spin mice. [150][151][152] Because pro-IL-1 is fully biologically active and constitutively expressed in a wide variety of cell types, understanding IL-1 cytokine biology, which remains significantly obscure, will shed more light on the pathogenesis of this inflammatory disorder and could provide much-needed targeted therapy for these rare diseases.…”