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.

Chronic recurrent multifocal osteomyelitis (CRMO) in humans can be modeled in Pstpip2cmo mice, which carry a missense mutation in the proline–serine–threonine phosphatase–interacting protein 2 (Pstpip2) gene. As cmo disease in mice, the experimental model analogous to human CRMO, is mediated specifically by IL-1β and not by IL-1α, delineating the molecular pathways contributing to pathogenic IL-1β production is crucial to developing targeted therapies. In particular, our earlier findings support redundant roles of NLR family pyrin domain-containing 3 (NLRP3) and caspase-1 with caspase-8 in instigating cmo. However, the signaling components upstream of caspase-8 and pro-IL-1β cleavage in Pstpip2cmo mice are not well-understood. Therefore, here we investigated the signaling pathways in these mice and discovered a central role of a nonreceptor tyrosine kinase, spleen tyrosine kinase (SYK), in mediating osteomyelitis. Using several mutant mouse strains, immunoblotting, and microcomputed tomography, we demonstrate that absent in melanoma 2 (AIM2), receptor-interacting serine/ threonine protein kinase 3 (RIPK3), and caspase recruitment domain–containing protein 9 (CARD9) are each dispensable for osteomyelitis induction in Pstpip2cmo mice, whereas genetic deletion of Syk completely abrogates the disease phenotype. We further show that SYK centrally mediates signaling upstream of caspase-1 and caspase-8 activation and principally up-regulates NF-κB and IL-1β signaling in Pstpip2cmo mice, thereby inducing cmo. These results provide a rationale for directly targeting SYK and its downstream signaling components in CRMO.

BACKGROUND: Public reporting of cardiac surgery ratings has been advocated to inform patient selection of hospitals. Although Society of Thoracic Surgeons (STS) ratings are based on audited riskadjusted patient outcomes, other rating systems rely on administrative databases. In this study, we evaluate correlation among 4 widely used hospital rating systems for coronary artery bypass grafting (CABG) and aortic valve replacement (AVR). STUDY DESIGN: We identified an initial cohort of 602 hospitals from US News & World Report's (USN) listing of the 2016-2017 "Best Hospitals for Cardiology & Heart Surgery." From this cohort, current publicly available CABG and AVR ratings were collected from the STS, USN, Centers for Medicare & Medicaid Services, and Healthgrades. All 4 rating systems rated hospitals as high, average, or below average performers for each procedure. We then determined the match rate between rating systems for individual hospitals and assessed interrater reliability with Cohen's k. RESULTS: Rating systems had different distributions of high and low performing ratings assigned. USN rated hospitals as high performing for both CABG and AVR more frequently compared with STS, Healthgrades, and Centers for Medicare & Medicaid Services. For CABG, the match rate between systems varied from 50% to 85%, with the best match between STS and Centers for Medicare & Medicaid Services. Similarly for AVR, the match rate varied from 50% to 73%, with the best match between STS and Healthgrades. Interrater reliability was poor among the 4 rating systems (k < 0.2) and consistent with no agreement for CABG and AVR ratings. CONCLUSIONS: Publicly reported cardiac surgery ratings have significant discrepancy and poor correlation. This might confuse instead of clarify public perception of hospital quality for cardiac surgery.