Abstract
Pyrin domain-only proteins (POPs) are recently evolved, primate-specific proteins demonstrated in vitro as negative regulators of inflammatory responses. However, their in vivo function is not understood. Of the four known POPs, only POP2 is reported to regulate NF-κB-dependent transcription and multiple inflammasomes. Here we use a transgenic mouse-expressing POP2 controlled by its endogenous human promotor to study the immunological functions of POP2. Despite having significantly reduced inflammatory cytokine responses to LPS and bacterial infection, POP2 transgenic mice are more resistant to bacterial infection than wild-type mice. In a pulmonary tularaemia model, POP2 enhances IFN-γ production, modulates neutrophil numbers, improves macrophage functions, increases bacterial control and diminishes lung pathology. Thus, unlike other POPs thought to diminish innate protection, POP2 reduces detrimental inflammation while preserving and enhancing protective immunity. Our findings suggest that POP2 acts as a high-order regulator balancing cellular function and inflammation with broad implications for inflammation-associated diseases and therapeutic intervention.
Highlights
Pyrin domain-only proteins (POPs) are recently evolved, primate-specific proteins demonstrated in vitro as negative regulators of inflammatory responses
Whether similar regulation occurs in vivo and how POP2 influences in vivo inflammatory responses are unknown
Using mice-expressing human POP2, this study confirms the anticipated in vivo functions of POP2, that NF-kB and Nlrp[3] inflammasome-dependent cytokine responses to inflammatory challenge and infection are tempered by POP2
Summary
Pyrin domain-only proteins (POPs) are recently evolved, primate-specific proteins demonstrated in vitro as negative regulators of inflammatory responses. Their in vivo function is not understood. Viral and mammalian Pyrin domain-containing proteins (PYDC) or Pyrin-only proteins (POPs), comprised of essentially a solitary PYD, have been identified as regulators of inflammatory processes by either inhibiting NF-kB p65 signalling, limiting inflammasome formation or both[5,6,7,8,9,10,11,12,13,14]. POP2 has a unique function in balancing detrimental and protective inflammatory responses during infection, thereby highlighting the importance of this human protein in inflammatory and infectious disease
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