Regnase-1 Deficiency Restrains Klebsiella pneumoniae Infection by Regulation of a Type I Interferon Response

Excessive inflammation can cause tissue damage and autoimmunity, sometimes accompanied by severe morbidity or mortality. Numerous negative feedback mechanisms exist to prevent unchecked inflammation, but this restraint may come at the cost of suboptimal infection control. Regnase-1 (MCPIP1), a feedback regulator of IL-17 and LPS signaling, binds and degrades target mRNAs. Consequently, Reg1 deficiency exacerbates autoimmunity in multiple models. However, the role of Reg1 in bacterial immunity remains poorly defined. Here, we show that mice deficient in Reg1 are resistant to Klebsiella pneumoniae (KP). Reg1 deficiency did not accelerate bacterial eradication. Rather, Reg1-deficient alveolar macrophages had elevated Ifnb1 and enrichment of type I IFN genes. Blockade of IFNR during KP infection reversed disease improvement. Reg1 did not impact Ifnb1 stability directly, but Irf7 expression was affected. Thus, Reg1 suppresses type I IFN signaling restricting resistance to KP, suggesting that Reg1 could potentially be a target in severe bacterial infections. IMPORTANCE Klebsiella pneumoniae (KP) can cause life-threatening bacterial pneumonia and is the third most common cause of ventilator-associated pneumonia in the United States. Host inflammatory responses to infection are necessary to control disease, yet at the same time can cause collateral damage or immunopathology. During immune responses, many events are established within the infected tissue to limit unchecked inflammation. However, this restraint of immunity can impair infection control, and it is not fully understood how this balance is maintained during different infection settings. In this study we explored the possibility that a host-derived negative regulator of RNA, Regnase-1, limits immunity to KP by dampening inflammation. Indeed, mice with reduced Regnase-1 levels showed improved survival to KP infection, linked to regulation of type I interferons. Therefore, although restraint of Reg1 is beneficial to prevent immunopathology, temporary blockade of Reg1 could potentially be exploited to improve host defense during infectious settings such as KP.