Progranulin aggravates lethal Candida albicans sepsis by regulating inflammatory response and antifungal immunity

Abstract

Candida albicans is the most frequent pathogen of fungal sepsis associated with substantial mortality in critically ill patients and those who are immunocompromised. Identification of novel immune-based therapeutic targets from a better understanding of its molecular pathogenesis is required. Here, we reported that the production of progranulin (PGRN) levels was significantly increased in mice after invasive C.albicans infection. Mice that lacked PGRN exhibited attenuated kidney injury and increased survival upon a lethal systemic infection with C. albicans. In mice, PGRN deficiency protected against systemic candidiasis by decreasing aberrant inflammatory reactions that led to renal immune cell apoptosis and kidney injury, and by enhancing antifungal capacity of macrophages and neutrophils that limited fungal burden in the kidneys. PGRN in hematopoietic cell compartment was important for this effect. Moreover, anti-PGRN antibody treatment limited renal inflammation and fungal burden and prolonged survival after invasive C. albicans infection. In vitro, PGRN loss increased phagocytosis, phagosome formation, reactive oxygen species production, neutrophil extracellular traps release, and killing activity in macrophages or neutrophils. Mechanistic studies demonstrated that PGRN loss up-regulated Dectin-2 expression, and enhanced spleen tyrosine kinase phosphorylation and extracellular signal-regulated kinase activation in macrophages and neutrophils. In summary, we identified PGRN as a critical factor that contributes to the immunopathology of invasive C.albicans infection, suggesting that targeting PGRN might serve as a novel treatment for fungal infection.

Characteristics and Clinical Prognosis of Septic Patients With Persistent Lymphopenia

“…The top 3 bacterial cultures were Acinetobacter baumannii, 35,36 Klebsiella pneumoniae and Pseudomonas aeruginosa, [37][38][39] and Monilia albican accounted for the highest proportion of fungal culture. 40,41 Acinetobacter baumannii, Klebsiella pneumonia, Pseudomonas aeruginosa, and Monilia albican are all opportunistic pathogens that are susceptible to infect patients with lower immune function and are prone to multidrug-resistant strains with higher levels of antimicrobial drug application after infection. 42 We hypothesized that septic patients with persistent lymphopenia might be immunosuppressed and vulnerable to pathogens, and therefore at higher risk of secondary infection.…”

The Immunomodulatory Activity of Punica granatum L. Peel Extract Increases the Lifespan of Mice with Lethal Sepsis

“…Cells from animals treated with P. granatum maintained H 2 O 2 production but at lower levels than those in the CLP group. Controlling the release of reactive oxygen species is relevant for avoiding microbial proliferation without generating tissue damage and therefore contributes to restoring immune homeostasis in septic animals [ 39 ].…”

Immune responses to human fungal pathogens and therapeutic prospects

“…Although neutrophils are protective during invasive candidiasis, their excessive accumulation and activation may also have detrimental effects, as seen in patients with neutropenia upon neutrophil recovery. Corticosteroids ameliorate inflammation and clinical symptoms in this setting, but certain immunopathogenic factors have been delineated in mice and humans -for example, the chemokine receptor CCR1, the CLR DNGR1, the endoribonuclease MCPIP1, the secreted growth factor progranulin and IFNγ -that show promise for eventually developing more selective therapeutic approaches 9,[53][54][55][56][57] . Moreover, immunopathology during renal candidiasis can be ameliorated through activation of the IL-17-dependent kallikrein-kinin system, which prevents renal tubular cell apoptosis and preserves kidney function 58 .…”