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The eye is regarded as an immune privileged site. Since the presence of a vasculature would impair vision, the vasculature of the eye is located outside of the central light path. As a result, many regions of the eye evolved mechanisms to deliver immune cells to sites of dysgenesis, injury, or in response to the many age-related pathologies. While the purpose of these immune responses is reparative or protective, cytokines released by immune cells compromise visual acuity by inducing inflammation and fibrosis. The response to traumatic or pathological injury is distinct in different regions of the eye. Age-related diseases impact both the anterior and posterior segment and lead to reduced quality of life and blindness. Here we focus attention on the role that inflammation and fibrosis play in the progression of age-related pathologies of the cornea and the lens as well as in glaucoma, the formation of epiretinal membranes, and in proliferative vitreoretinopathy. [ABSTRACT FROM AUTHOR]

Abstract: Amyloid-β (Aβ) is produced through the enzymatic cleavage of amyloid precursor protein (APP) by β (Bace1) and γ-secretases. The accumulation and aggregation of Aβ as amyloid plaques is the hallmark pathology of Alzheimer׳s disease and has been found in other neurological disorders, such as traumatic brain injury and multiple sclerosis. Although the role of Aβ after injury is not well understood, several studies have reported a negative correlation between Aβ formation and functional outcome. In this study we show that levels of APP, the enzymes cleaving APP (Bace1 and γ-secretase), and Aβ are significantly increased from 1 to 3 days after impact spinal cord injury (SCI) in mice. To determine the role of Aβ after SCI, we reduced or inhibited Aβ in vivo through pharmacological (using DAPT) or genetic (Bace1 knockout mice) approaches. We found that these interventions significantly impaired functional recovery as evaluated by white matter sparing and behavioral testing. These data are consistent with a beneficial role for Aβ after SCI. [Copyright &y& Elsevier]

ADAMTS5 has been implicated in the degradation of cartilage aggrecan in human osteoarthritis. Here, we describe a novel role for the enzyme in the regulation of TGFβ1 signaling in dermal fibroblasts both in vivo and in vitro. Adamts5-/- mice, generated by deletion of exon 2, exhibit impaired contraction and dermal collagen deposition in an excisional wound healing model. This was accompanied by accumulation in the dermal layer of cell aggregates and fibroblastic cells surrounded by a pericellular matrix enriched in full-length aggrecan. Adamts5-/- wounds exhibit low expression (relative to wild type) of collagen type I and type III but show a persistently elevated expression of tgfbRII and alk1. Aggrecan deposition and impaired dermal repair in Adamts5-/- mice are both dependent on CD44, and Cd44-/-/Adamts5-/- mice display robust activation of TGFβ receptor II and collagen type III expression and the dermal regeneration seen in WT mice. TGFβ1 treatment of newborn fibroblasts from wild type mice results in Smad2/3 phosphorylation, whereas cells from Adamts5-/- mice phosphorylate Smad1/5/8. The altered TGFβ1 response in the Adamts5-/- cells is dependent on the presence of aggrecan and expression of CD44, because Cd44-/-/Adamts5-/- cells respond like WT cells. We propose that ADAMTS5 deficiency in fibrous tissues results in a poor repair response due to the accumulation of aggrecan in the pericellular matrix of fibroblast progenitor cells, which prevents their transition to mature fibroblasts. Thus, the capacity of ADAMTS5 to modulate critical tissue repair signaling events suggests a unique role for this enzyme, which sets it apart from other members of the ADAMTS family of proteases. [ABSTRACT FROM AUTHOR]

The wound microenvironment comprises constituents, such as the extracellular matrix (ECM), that regulate with temporal and spatial precision, the migratory, proliferative, and contractility of wound cells. Prompt closure of the wound is an early and critical phase of healing and β1 integrins are important in this process. We previously reported a marked increase in integrin α9β1 expression in epidermal keratinocytes in cutaneous and corneal wounds. However, the functional role of keratinocyte α9β1 during re-epithelialization is unknown and analysis has been precluded by the lethal phenotype of integrin α9β1 knockout mice. We now report that in conditional integrin α9 knockout (K14-α9 null) mice, normal proliferation occurs in epidermal keratinocytes and corneal basal cells. Normal epidermal keratinocyte morphology is also retained. However, corneal basal cell morphology and epithelial thickness are altered, suggesting that loss of integrin α9β1 results in abnormal corneal differentiation. In cutaneous wounds, the number of proliferating epidermal keratinocytes is significantly reduced in K14-α9 null mice compared with α9fl/− mice, but not in Cre (control) mice. The decreased keratinocyte proliferation observed in K14-α9 null mice negatively impacts healing, resulting in a thinner migrating epithelium, demonstrating that α9β1 is crucial for efficient and proper re-epithelialization during cutaneous wound healing.Journal of Investigative Dermatology (2009) 129, 217–228; doi:10.1038/jid.2008.201; published online 17 July 2008 [ABSTRACT FROM AUTHOR]

The fibronectins (FN) comprise a family of adhesive extracellular matrix proteins thought to mediate important functions in cutaneous wounds. Plasma fibronectin (pFN) extravasates for days from intact hyperpermeable vessels following injury whereas mRNAs encoding the cellular fibronectins (cFN) that include two segments, termed EIIIA (EDA) and EIIIB (EDB), are expressed by wound cells. Wounds in mice null for pFN appear to heal normally whereas those in EIIIA null mice exhibit defects, suggesting that cFN may play a role when pFN is missing. Integrinα9β1, a receptor for several extracellular matrix proteins as well as the EIIIA segment, is expressed normally in the basal layer of squamous epithelia. We report results from immunohistochemistry on healing wounds demonstrating that EIIIA-containing cFN are deposited abundantly but transiently from day 4 to 7 whereas EIIIB-containing cFN persist at least through day 14. Elevated expression ofα9β1 is seen in basal and suprabasal epidermal keratinocytes in wounds. The spatial expression patterns of cFN andα9β1 are distinct, but overlap in the dermal–epidermal junction, and both are expressed contemporaneously. These observations suggest a role forα9β1–EIIIA interactions in wound keratinocyte function. [ABSTRACT FROM AUTHOR]