Single Immunoglobulin Interleukin-1 Receptor-Related Molecule Impairs Host Defense during Pneumonia and Sepsis Caused by <b><i>Streptococcus Pneumoniae</i></b>

Abstract

Streptococcus pneumoniae is a common cause of pneumonia and sepsis. Toll-like receptors (TLRs) play a pivotal role in the host defense against infection. In this study, we sought to determine the role of single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR a.k.a. TIR8), a negative regulator of TLR signaling, in pneumococcal pneumonia and sepsis. Wild-type and SIGIRR-deficient (sigirr-/-) mice were infected intranasally (to induce pneumonia) or intravenously (to induce primary sepsis) with S. pneumoniae and euthanized after 6, 24, or 48 h for analyses. Additionally, survival studies were performed. sigirr-/- mice showed delayed mortality during lethal pneumococcal pneumonia. Accordingly, sigirr-/- mice displayed lower bacterial loads in lungs and less dissemination of the infection 24 h after the induction of pneumonia. SIGIRR deficiency was associated with increased interstitial and perivascular inflammation in lung tissue early after infection, with no impact on neutrophil recruitment or cytokine production. sigirr-/- mice also demonstrated reduced bacterial burdens at multiple body sites during S. pneumoniae sepsis. sigirr-/- alveolar macrophages and neutrophils exhibited an increased capacity to phagocytose viable pneumococci. These results suggest that SIGIRR impairs the antibacterial host defense during pneumonia and sepsis caused by S. pneumoniae.

Divergent Functions of Toll-like Receptors during Bacterial Lung Infections

“…(Figure 2). Similarly, the importance of single immunoglobulin IL-1 receptor-related molecule (SIGIRR), a transmembrane molecule that inhibits TLR signaling, in attenuating the antibacterial response was observed in pneumococcal pneumonia (63), whereas its deficiency proved beneficial for survival and bacterial clearance during P. aeruginosa-induced pneumonia (64), indicating the nonredundant but specific role of this negative regulator in lower respiratory tract infection. Additionally, S. pneumoniae and Klebsiella both exploit host IRAK-M, a regulator that inhibits the activity of IRAKs, to evade pulmonary immune responses (65,66).…”

Tuning inflammation and immunity by the negative regulators IL‐1R2 and IL‐1R8

“…Also in a human bladder epithelial cell line (BECs), IL‐1R8 silencing caused increased LPS‐induced JNK, p38 and ERK1/2 activation and IL‐6 and IL‐8 production . Similarly, in Streptococcus pneumoniae pneumonia and sepsis , IL‐1R8 deficiency was associated with reduced mortality, bacterial load, and dissemination …”

“…101 Similarly, in Streptococcus pneumoniae pneumonia and sepsis, IL-1R8 deficiency was associated with reduced mortality, bacterial load, and dissemination. 143 In Citrobacter rodentium infection in mice, that resembles intestinal infections by enteric bacterial pathogens in humans, IL-1R8 deficiency induced an enhanced IL-1R1 and MyD88-dependent proinflammatory and anti-microbial response, that was however responsible of microbiota depletion and consequently favored pathogen colonization. 144 Thus, depending on the effect of inflammatory responses in specific infections, IL-1R8 may play beneficial or detrimental role in the innate resistance to pathogens, emerging as a key player in the maintenance of the equilibrium between protective immune responses and inflammation and host injury.…”

A protective role of IL-37 in cancer: a new hope for cancer patients

“…Consistent with those results, TIR-8 KO mice display lower bacterial growth and dissemination in their bodies and decreased mortality. Their macrophages exhibit enhanced phagocytosis [51]. The absence of TIR-8 has also been shown to provoke exaggerated local and systemic inflammatory responses, pathology, and mortality in Pseudomonas aeruginosa infections of lungs in mice [52].…”