TNF-stimulated gene 6 promotes formation of hyaluronan–inter-α-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness

Abstract

Exposure to pollutants, such as ozone, exacerbates airway inflammation and hyperresponsiveness (AHR). TNF-stimulated gene 6 (TSG-6) is required to transfer inter-α-inhibitor heavy chains (HC) to hyaluronan (HA), facilitating HA receptor binding. TSG-6 is necessary for AHR in allergic asthma, because it facilitates the development of a pathological HA-HC matrix. However, the role of TSG-6 in acute airway inflammation is not well understood. Here, we hypothesized that TSG-6 is essential for the development of HA- and ozone-induced AHR. TSG-6 and TSG-6 mice were exposed to ozone or short-fragment HA (sHA), and AHR was assayed via flexiVent. The AHR response to sHA was evaluated in the isolated tracheal ring assay in tracheal rings from TSG-6 or TSG-6, with or without the addition of exogenous TSG-6, and with or without inhibitors of Rho-associated, coiled-coil-containing protein kinase (ROCK), ERK, or PI3K. Smooth-muscle cells from mouse tracheas were assayed for signaling pathways. We found that TSG-6 deficiency protects against AHR after ozone () or sHA ( and ) exposure. Moreover, TSG-6 tracheal ring non-responsiveness to sHA was reversed by exogenous TSG-6 addition. sHA rapidly activated RhoA, ERK, and Akt in airway smooth-muscle cells, but only in the presence of TSG-6. Inhibition of ROCK, ERK, or PI3K/Akt blocked sHA/TSG-6-mediated AHR. In conclusion, TSG-6 is necessary for AHR in response to ozone or sHA, in part because it facilitates rapid formation of HA-HC complexes. The sHA/TSG-6 effect is mediated by RhoA, ERK, and PI3K/Akt signaling.

Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI3K/Akt1 pathway

“…37 Moreover, inhibition of PI3K/Akt signalling pathways have been shown to block tumour necrosis factor-stimulated gene 6-mediated acute airway inflammation and hyper-responsiveness in response to ozone or short-fragment HA. 38 Here we confirm that the inclusion of PI3K as an upstream activator of Akt1 was confirmed by using specific inhibitors, wortmannin and LY2940002, which consistently suppressed Akt1 phosphorylation and neutrophil counts. Akt1 is regulated by PI3K in LMMHA-induced neutrophil responses.…”

Anti-inflammatory protein TNFα-stimulated gene-6 (TSG-6) reduces inflammatory response after brain injury in mice

“…Our recent study identi ed that TSG-6 is expressed in the central nervous system (CNS), where it catalyzes the transfer of heavy chains (HCs) from Inter-a-Inhibitor (IaI, also known as ITI) onto HA, forming a specialized HA/HC/TSG-6 matrix within the glial scar, but the role of this specialized matrix within the glial scar remains to be established (42,(48)(49)(50)(51)(52). The HA/HC/TSG-6 matrix has been shown to be monocyte-adhesive and is found in most, if not all, in ammatory processes (53,54). These TSG-6 modi ed HA matrices bind in ammatory cells, and the interaction of these cells with the HA matrices modulates their responses, which are central to pathological in ammation (55)(56)(57)(58)(59)(60)(61).…”

Anti-inflammatory protein TNFα-stimulated gene-6 (TSG-6) reduces inflammatory response after brain injury in mice

“…We recently identified that TSG-6 is expressed in the central nervous system (CNS), where it catalyzes the transfer of HCs from Inter-a-Inhibitor (IαI, also known as ITI) onto HA, forming a specialized HA/HC/TSG-6 matrix within the glial scar (47)(48)(49)(50)(51)(52). This HA/HC/TSG-6 matrix is monocyte-adhesive and is found in most, if not all, inflammatory processes (53,54). These TSG-6 modified HA matrices bind inflammatory cells, and the interaction of these cells with the HA matrices modulates their responses, which are central to pathological inflammation (55)(56)(57)(58)(59)(60)(61).…”