Chitinase 3-Like 1 Promotes Candida albicans Killing and Preserves Corneal Structure and Function by Controlling Host Antifungal Responses

Abstract

Chitinase 3-like 1 (CHI3L1) has been shown to play a role in promoting antibacterial responses, decreasing tissue injury, and enhancing pulmonary repair. This study sought to elucidate the role of CHI3L1 in augmenting the corneal innate immune response to Candida albicans infection in an animal model of fungal keratitis. Flagellin applied topically 24 h prior to C. albicans inoculation significantly protected the corneal from C. albicans and induced CHI3L1 expression in C57BL/6 mouse corneas. CHI3L1, however, played a detectable but minor role in flagellin-induced protection. While C. albicans keratitis was more severe in the corneas treated with Chi3l1 small interfering RNA (siRNA), corneas treated with recombinant CHI3L1 before C. albicans inoculation had markedly ameliorated keratitis, reduced fungal load, and decreased polymorphonucleocyte (PMN) infiltration in an interleukin 13 receptor ␣2 (IL-13R␣2)-dependent manner. CHI3L1 treatment resulted in the induction of the antimicrobial peptides ␤-defensin 3, CRAMP, and chemokine CXCL10 and its receptor CXCR3 in corneal epithelial cells. Importantly, CHI3L1 administered after C. albicans inoculation also had strong protection against fungal keratitis, suggesting a therapeutic window. This is the first report demonstrating that CHI3L1 is induced during fungal infection, where it acts as an immunomodulator to promote fungal clearance and to regulate antifungal innate immune responses in the cornea.T he cornea's visual properties are exquisitely sensitive to inflammation-mediated damage. The cornea is an immuneprivileged site with multiple anatomical, physiological, and immunoregulatory processes that inhibit many innate and adaptive immune responses (1, 2). As such, a normal cornea is remarkably resistant to infection. However, when the epithelial barrier function is breached (3), which may occur during routine contact lens wear, opportunistic pathogens such as bacteria and fungi gain access to the deeper cellular layers of the epithelium and colonize the cornea (4). This leads to the engagement of intraepithelially expressed Toll-like receptors (TLRs) with invading pathogens (5), resulting in the abrogation of immune privilege and the reactivation of the innate immune response (6). Candida albicans is one such opportunistic pathogen that may cause corneal infection following trauma or surgery or under immunosuppressive conditions, such as the prolonged use of corticosteroids and topical anesthetic abuse (7-12). Although the fungal keratitis is rare, the incidence has increased in recent years, especially in contact lens wearers (13,14). To date, there is no clinically amenable measure to prevent fungal keratitis. Current practice in treating fungal keratitis involves the use of topical antifungal drops, such as natamycin and amphotericin B. Topical antifungals can have toxic effects, such as punctate keratitis and recurrent corneal epithelial erosions (15). Hence, understanding the pathogenesis of fungal keratitis and host responses will aid in identifying new the...

Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas

“…Compared with the controls, the presence of IL-1b neutralizing antibody significantly delayed corneal epithelium-wound closure ( Figure 2, A and B). We then performed siRNA knockdown of IL-1Ra via subconjunctival injection 30 in NL mice. IL-1Ra knockdown resulted in much-delayed wound healing compared with control siRNA-treated mice.…”

Setting off the Alarms: Candida albicans Elicits Pro-Inflammatory Differential Gene Expression in Intestinal Peyer’s Patches

“…The C-type lectin DC-SIGN, which was upregulated 17.5-fold, is an important innate immune receptor expressed on phagocytes such as dendritic cells DCs, and has been demonstrated to recognize N-linked mannans on C. albicans (35-37). Chitinase-like protein 3 (Chil3), which was upregulated 31.5-fold, is a pseudo-chitinase that promotes C. albicans killing (38). It is expressed by intestinal epithelial cells (IECs) and macrophages in inflamed intestines (39).…”

Osteopontin contributes to effective neutrophil recruitment, IL‐1β production and apoptosis in Aspergillus fumigatus keratitis

“…Furthermore, neutrophils were shown to be the first cells recruited to the cornea to fight fungal infection . Human corneal epithelial cells are involved in antifungal immunity by way of releasing antimicrobial peptides, inflammatory cytokines and chemokines . The role of OPN in human neutrophils and macrophages in antifungal immunity has been described, but OPN has not previously been examined corneal epithelial cells solely involved in corneal wound healing .…”

“…24 Human corneal epithelial cells are involved in antifungal immunity by way of releasing antimicrobial peptides, inflammatory cytokines and chemokines. 25,26 The role of OPN in human neutrophils and macrophages in antifungal immunity has been described, but OPN has not previously been examined corneal epithelial cells solely involved in corneal wound healing. 27 Importantly, our study demonstrates that human corneal epithelial cells participate in antifungal immunity by producing OPN.…”