Crosstalk Between T Lymphocytes and Lung Fibroblasts: Generation of a Hyaluronan-Enriched Extracellular Matrix Adhesive for Monocytes

Abstract

In immunity and inflammation, T cells are often associated with stromal mesenchymal cells such as fibroblasts. Hyaluronan and proteins that associate with hyaluronan such as versican and tumor necrosis factor-inducible gene-6 (TSG-6) are extracellular matrix (ECM) components that promote leukocyte adhesion, accumulation, and activation. However, the factors responsible for producing this specialized ECM and its impact on inflammatory events are not well understood. In this study, we explored the role of T cells in stimulating lung fibroblasts to produce an ECM that impacts monocyte adhesion. We found that CD3/CD28-activated human CD4+ T cells when co-cultured with human lung fibroblasts stimulated the expression of mRNA for hyaluronan synthase 2 (HAS2) and decreased the expression of hyaluronidase 2 (HYAL2). This led to an increase in the deposition of hyaluronan that formed cable-like structures within the ECM. Co-culturing activated T cells with fibroblasts also led to increased expression and accumulation of TSG-6. Surprisingly, addition of activated CD4+ T cells to the fibroblasts reduced the expression of mRNA for versican, and increased the expression of enzymes that degrade versican, such as ADAMTS-4 and ADAMTS-9 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif) leading to a decrease in versican in the ECM of the co-cultures. Furthermore, addition of human monocytes to these co-cultures resulted in elevated monocyte adhesion to the cable-like structures in the ECM when compared to controls. These results illustrate the importance of crosstalk between T cells and fibroblasts in promoting the generation of a matrix that is adhesive for monocytes.

Intratendon delivery of leukocyte‐rich platelet‐rich plasma at early stage promotes tendon repair in a rabbit Achilles tendinopathy model

“…The additional inflammation stimulates fibroblast to cause a rapid production of cytokines such as IL‐6, IL‐8, and cyclooxygenase‐2 (Dakin et al, ). Furthermore, the leukocyte in Lr‐PRP would interacted with extracellular matrix components in tissues to provide costimulatory signals that enhance immune response at the site of inflammation (Gaucherand et al, ). Our findings indicated that an overstimulation of the immune system had disadvantageous effects on tissue repair.…”

Versican—A Critical Extracellular Matrix Regulator of Immunity and Inflammation

“…Complexes form as a result of this interaction which shape the microenvironment which impacts immunity and inflammation (95,96,(109)(110)(111)(112)(113). Versican is usually found co-localized with hyaluronan, however, inflammatory situations exist where each can be found separately (114,115). Like versican, hyaluronan is also well-known for having both pro-and anti-inflammatory properties [reviewed in (95,96,111,113,116,117)].…”

“…Using agonists that promote ER stress, these models demonstrated that stromal cells produce an ECM organized into cable like structures that bound leukocytes [see reviews (96,116,137)]. These cable-like structures contain hyaluronan, versican, TSG-6, and IαI that bind different subsets of leukocytes (93,94,112,(114)(115)(116)(137)(138)(139)(140)(141)(142)(143)(144)(145)(146)(147). Such structures have not only been found in vitro, but also in diseased tissues, such as in atherosclerosis (10,84), inflammatory bowel disease (IBD) (94), and in brain and spinal cord injury (53,91).…”

The consequence of matrix dysfunction on lung immunity and the microbiome in COPD

“…Low-molecular hyaluronan interacts with CD44 and RHAMM [56], and this interaction may cause macrophage retention in the airspaces. Similarly, activated T-cells induce hyaluronan production by human fibroblasts that results in cable-like structures of matrix that trap monocytes [57]. IL-1β also induces a hyaluronan-rich ECM from fibroblasts that promotes monocyte binding [58].…”