Susmit Suvas

IL-2/Anti–IL-2 Antibody Complex Treatment Inhibits the Development but Not the Progression of Herpetic Stromal Keratitis

The IL-2/anti–IL-2 Ab immunocomplex has recently been shown to expand the naturally occurring pool of CD4+Foxp3+ regulatory T cells (Tregs). In this study, we show that administration of the IL-2/anti–IL-2 Ab immunocomplex to C57BL/6 mice, prior to corneal HSV-1 infection, significantly increased the pool of Foxp3+ Tregs when measured at early time points postinfection. Increased numbers of Foxp3+ Tregs on days 2 and 4 postinfection resulted in a marked reduction in the development of severe herpetic stromal keratitis (HSK). When compared with corneas from the control group, corneas from the immunocomplex-treated group showed a significant reduction in the amount of infectious virus on day 2 but not on day 4 postinfection. Reduced viral load was associated with a 2-fold increase in NK cell numbers in corneas from the immunocomplex-treated group of mice. Moreover, a dramatic reduction in the influx of CD4 T cells in inflamed corneas was determined on days 7 and 16 postinfection in the immunocomplex-treated group of infected mice. Immunocomplex treatment given on days 5, 6, and 7 postinfection significantly increased Foxp3+ Tregs in draining lymph nodes and in the spleen but failed to reduce the severity of HSK. In terms of the influx of CD4 T cells and granulocytes into inflamed corneas, no significant differences were noted between both groups of mice on day 16 postinfection. Our findings demonstrate that increasing Foxp3+ Tregs early but not late postinfection in secondary lymphoid tissues is more efficacious in controlling the severity of HSK.

Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis

Substance P (SP) is an undecapeptide present in the CNS and the peripheral nervous system. SP released from the peripheral nerves exerts its biological and immunological activity via high-affinity neurokinin 1 receptor (NK1R). SP is also produced by immune cells and acts as an autocrine or paracrine fashion to regulate the function of immune cells. In addition to its proinflammatory role, SP and its metabolites in combination with insulin-like growth factor-1 are shown to promote the corneal epithelial wound healing. Recently, we showed an altered ocular surface homeostasis in unmanipulated NK1R−/− mice, suggesting the role of SP-NK1R signaling in ocular surface homeostasis under steady-state. This review summarizes the immunobiology of SP and its effect on immune cells and immunity to microbial infection. In addition, the effect of SP in inflammation, wound healing, and corneal epithelial homeostasis in the eye is discussed.

Loss of Neurokinin-1 Receptor Alters Ocular Surface Homeostasis and Promotes an Early Development of Herpes Stromal Keratitis

Substance P neuropeptide and its receptor, neurokinin-1 receptor (NK1R), are reported to present on the ocular surface. In this study, mice lacking functional NK1R exhibited an excessive desquamation of apical corneal epithelial cells in association with an increased epithelial cell proliferation and increased epithelial cell density, but decreased epithelial cell size. The lack of NK1R also resulted in decreased density of corneal nerves, corneal epithelial dendritic cells (DCs), and a reduced volume of basal tears. Interestingly, massive accumulation of CD11c+CD11b+ conventional DCs was noted in the bulbar conjunctiva and near the limbal area of corneas from NK1R−/− mice. After ocular HSV-1 infection, the number of conventional DCs and neutrophils infiltrating the infected corneas was significantly higher in NK1R−/− than C57BL/6J mice. This was associated with an increased viral load in infected corneas of NK1R−/− mice. As a result, the number of IFN-γ–secreting virus-specific CD4 T cells in the draining lymph nodes of NK1R−/− mice was much higher than in infected C57BL/6J mice. An increased number of CD4 T cells and mature neutrophils (CD11b+Ly6ghigh) in the inflamed corneas of NK1R−/− mice was associated with an early development of severe herpes stromal keratitis. Collectively, our results show that the altered corneal biology of uninfected NK1R−/− mice along with an enhanced immunological response after ocular HSV-1 infection causes an early development of herpes stromal keratitis in NK1R−/− mice.

Challenges of corneal infections

ABSTRACT Introduction: Ocular infections remain an important cause of blindness worldwide and represent a challenging public health concern. In this regard, microbial keratitis due to fungal, bacterial, or viral infection can result in significant vision loss secondary to corneal scarring or surface irregularity. Left untreated corneal perforation and endophthalmitis can result, leading to loss of the eye. Rigorously studied animal models of disease pathogenesis have provided novel information that suggests new modes of treatment that may be efficacious clinically and emerging clinical data is supportive of some of these discoveries. Areas covered: This review focuses on advances in our understanding of disease pathogenesis in animal models and clinical studies and how these relate to improved clinical treatment. We also discuss a novel approach to treatment of microbial keratitis due to infection with these bacterial pathogens using PACK-CXL and recommend increased basic and clinical studies to address and refine the efficacy of this procedure. Expert commentary: Because resistance to antibiotics has developed over time to these bacterial pathogens, caution must be exercised in treatment. Attractive novel modes of treatment that hold new promise for further investigation include lipid based therapy, as well as use of small molecules that bind deleterious specific host responsive molecules and use of microRNA based therapies.

Immunoregulatory role of 15-lipoxygenase in the pathogenesis of bacterial keratitis

Although autacoids primarily derived from the cyclooxygenase‐2 and 5‐lipoxygenase (LOX) pathways are essential mediators of inflammation, endogenous specialized proresolving mediators (SPMs) act as robust agonists of resolution. SPM biosynthesis is initiated by the conversion of arachidonic acid, eicosa‐pentaenoic acid, and docosahexaenoic acid primarily via the 12/15‐LOX pathway. Although 12/15‐LOX activity is prominent in the cornea, the role of SPM pathway activation during infection remains largely unknown and is the focus of the current study. Pseudomonas keratitis was induced in resistant BALB/c and susceptible C57BL/6 (B6) mice. Biosynthetic pathways for proinflammatory autacoids and SPMs were assessed. Divergent lipid mediator profiles demonstrate the importance of 15‐LOX pathways in the pathogenesis of ocular infectious disease. Results indicate that an imbalance of LOX enzymatic pathways contributes to susceptibility observed in B6 mice where deficient activation of SPM circuits, as indicated by reduced 15‐hydroxy‐eicosatetraenoic acid and 17‐hydroxydocosahexaenoic acid levels, prevented transition toward resolution and led to chronic inflammation. In sharp contrast, BALB/c mice demonstrated a well‐balanced axis of 5‐LOX/12‐LOX/15‐LOX pathways, resulting in sufficient proresolving bioactive metabolite formation and immune homeostasis. Furthermore, a novel immunoregulatory role for 15‐LOX was revealed in inflammatory cells (polymorphonuclear leukocytes and macrophages), which influenced phagocytic activity. These data provide evidence that SPM circuits are essential for host defense during bacterial keratitis.—Carion, T.W., Greenwood, M., Ebrahim, A. S., Jerome, A., Suvas, S., Gronert, K., Berger, E. A. Immunoregulatory role of 15‐lipoxygenase in the pathogenesis of bacterial keratitis. FASEB J. 32, 5026–5038 (2018). www.fasebj.org