CXCR1-mediated neutrophil degranulation and fungal killing promote Candida clearance and host survival

Abstract

Systemic Candida albicans infection causes high morbidity and mortality and is now the leading cause of nosocomial bloodstream infection in the US. Neutropenia is a major risk factor for poor outcome in infected patients; however, the molecular factors that mediate neutrophil trafficking and effector function during infection are poorly defined. Here, using a mouse model of systemic candidiasis, we found that the neutrophil-selective CXC chemokine receptor Cxcr1 and its ligand, Cxcl5, are highly induced in the Candida-infected kidney, the target organ in the model. To investigate the role of Cxcr1 in antifungal host defense in vivo, we generated Cxcr1−/− mice and analyzed their immune response to Candida. Mice lacking Cxcr1 exhibited decreased survival with enhanced Candida growth in the kidney and renal failure. Surprisingly, increased susceptibility of Cxcr1−/− mice to systemic candidiasis was not due to impaired neutrophil trafficking from the blood into the infected kidney but was the result of defective killing of the fungus by neutrophils that exhibited a cell-intrinsic decrease in degranulation. In humans, the mutant CXCR1 allele CXCR1-T276 results in impaired neutrophil degranulation and fungal killing and was associated with increased risk of disseminated candidiasis in infected patients. Together, our data demonstrate a biological function for mouse Cxcr1 in vivo and indicate that CXCR1-dependent neutrophil effector function is a critical innate protective mechanism of fungal clearance and host survival in systemic candidiasis.

CXCR2 is critical for bacterial control and development of joint damage and pain in Staphylococcus aureus‐induced septic arthritis in mouse

“…Nevertheless, we did not detect bacteremia in DF2156A-treated mice (data not shown). Our data corroborate with some publications in which human neutrophils improved the efficacy to kill Pseudomonas aeruginosa [38] and Candida albicans [39] by CXCR1/2 activation. To check for a direct role of CXCR1/2 in the activation of neutrophils to control S. aureus infection, we demonstrated that the local treatment with DF2156A increased the bacterial load in the joint.…”

Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

“…A potential role of CXCR2 in activation is supported by studies showing that CXCR2 activates neutrophil killing by neutrophil extracellular traps (NETs) and is specifically required against C. albicans hyphae (47,49). The recruitment-independent activity of chemokine receptors has also been observed in murine CXCR1 deficiency and may therefore be a widely used potentiator of efficient killing (53).…”

Attenuation of murine allergic airway inflammation with a CXCR1/CXCR2 chemokine receptor inhibitor

“…To test our hypothesis, we selected reparixin to perform a proof of concept study to elucidate the role of the CXCR1/CXCR2 inhibitor in an animal model of cat dander extract (CDE)‐induced innate and allergic lung inflammation. While the functionality of CXCR2 has been extensively reported in mice, it was the recent demonstration of functional CXCR1 receptors in mice that provided the critical rationale for using mice to test our hypothesis. Wild‐type (WT) naïve mice were subjected to a CDE single challenge model, CDE‐SCM, Figure A, by challenging them once with CDE and evaluating markers for innate inflammation were quantified 16 hours later in BALF .…”