Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP.
Ozone exposure is associated with exacerbation of reactive airways disease. We have previously reported that the damage-associated molecular pattern, hyaluronan, is required for the complete biological response to ambient ozone and that hyaluronan fragments signal through toll-like receptor 4 (TLR4)...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3208559?pdf=render |
| _version_ | 1817968051199410176 |
|---|---|
| author | Zhuowei Li Erin N Potts-Kant Stavros Garantziotis W Michael Foster John W Hollingsworth |
| author_facet | Zhuowei Li Erin N Potts-Kant Stavros Garantziotis W Michael Foster John W Hollingsworth |
| author_sort | Zhuowei Li |
| collection | DOAJ |
| description | Ozone exposure is associated with exacerbation of reactive airways disease. We have previously reported that the damage-associated molecular pattern, hyaluronan, is required for the complete biological response to ambient ozone and that hyaluronan fragments signal through toll-like receptor 4 (TLR4). In this study, we further investigated the role of TLR4 adaptors in ozone-induced airway hyperresponsiveness (AHR) and the direct response to hyaluronan fragments (HA). Using a murine model of AHR, C57BL/6J, TLR4-/-, MyD88-/-, and TIRAP-/- mice were characterized for AHR after exposure to either ozone (1 ppm × 3 h) or HA fragments. Animals were characterized for AHR with methacholine challenge, cellular inflammation, lung injury, and production of pro-inflammatory cytokines. Ozone-exposed C57BL/6J mice developed cellular inflammation, lung injury, pro-inflammatory cytokines, and AHR, while mice deficient in TLR4, MyD88 or TIRAP demonstrated both reduced AHR and reduced levels of pro-inflammatory cytokines including TNFα, IL-1β, MCP-1, IL-6 and KC. The level of hyaluronan was increased after inhalation of ozone in each strain of mice. Direct challenge of mice to hyaluronan resulted in AHR in C57BL/6J mice, but not in TLR4-/-, MyD88-/-, or TIRAP-/- mice. HA-induced cytokine production in wild-type mice was significantly reduced in TLR4-/-, MyD88-/-, or TIRAP-/- mice. In conclusion, our findings support that ozone-induced airway hyperresponsiveness is dependent on the HA-TLR4-MyD88-TIRAP signaling pathway. |
| first_indexed | 2024-04-13T20:02:55Z |
| format | Article |
| id | doaj.art-545aa47d54c74b10aad7a7c775c3541f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T20:02:55Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-545aa47d54c74b10aad7a7c775c3541f2022-12-22T02:32:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01611e2713710.1371/journal.pone.0027137Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP.Zhuowei LiErin N Potts-KantStavros GarantziotisW Michael FosterJohn W HollingsworthOzone exposure is associated with exacerbation of reactive airways disease. We have previously reported that the damage-associated molecular pattern, hyaluronan, is required for the complete biological response to ambient ozone and that hyaluronan fragments signal through toll-like receptor 4 (TLR4). In this study, we further investigated the role of TLR4 adaptors in ozone-induced airway hyperresponsiveness (AHR) and the direct response to hyaluronan fragments (HA). Using a murine model of AHR, C57BL/6J, TLR4-/-, MyD88-/-, and TIRAP-/- mice were characterized for AHR after exposure to either ozone (1 ppm × 3 h) or HA fragments. Animals were characterized for AHR with methacholine challenge, cellular inflammation, lung injury, and production of pro-inflammatory cytokines. Ozone-exposed C57BL/6J mice developed cellular inflammation, lung injury, pro-inflammatory cytokines, and AHR, while mice deficient in TLR4, MyD88 or TIRAP demonstrated both reduced AHR and reduced levels of pro-inflammatory cytokines including TNFα, IL-1β, MCP-1, IL-6 and KC. The level of hyaluronan was increased after inhalation of ozone in each strain of mice. Direct challenge of mice to hyaluronan resulted in AHR in C57BL/6J mice, but not in TLR4-/-, MyD88-/-, or TIRAP-/- mice. HA-induced cytokine production in wild-type mice was significantly reduced in TLR4-/-, MyD88-/-, or TIRAP-/- mice. In conclusion, our findings support that ozone-induced airway hyperresponsiveness is dependent on the HA-TLR4-MyD88-TIRAP signaling pathway.http://europepmc.org/articles/PMC3208559?pdf=render |
| spellingShingle | Zhuowei Li Erin N Potts-Kant Stavros Garantziotis W Michael Foster John W Hollingsworth Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. PLoS ONE |
| title | Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. |
| title_full | Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. |
| title_fullStr | Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. |
| title_full_unstemmed | Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. |
| title_short | Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. |
| title_sort | hyaluronan signaling during ozone induced lung injury requires tlr4 myd88 and tirap |
| url | http://europepmc.org/articles/PMC3208559?pdf=render |
| work_keys_str_mv | AT zhuoweili hyaluronansignalingduringozoneinducedlunginjuryrequirestlr4myd88andtirap AT erinnpottskant hyaluronansignalingduringozoneinducedlunginjuryrequirestlr4myd88andtirap AT stavrosgarantziotis hyaluronansignalingduringozoneinducedlunginjuryrequirestlr4myd88andtirap AT wmichaelfoster hyaluronansignalingduringozoneinducedlunginjuryrequirestlr4myd88andtirap AT johnwhollingsworth hyaluronansignalingduringozoneinducedlunginjuryrequirestlr4myd88andtirap |