The Development of Early Host Response to Pseudomonas aeruginosa Lung Infection Is Critically Dependent on Myeloid Differentiation Factor 88 in Mice

Toll-like receptors (TLR) induce distinct patterns of host responses through myeloid differentiation factor 88 (MyD88)-dependent and/or -independent pathways, depending on the nature of the pathogen. Pseudomonas aeruginosa is a cause of serious lung infection in immunocompromised individuals and cystic fibrosis patients. The role of the TLR-MyD88 pathway in P. aeruginosa-induced lung infection in vivo was examined in this study. MyD88-/- mice demonstrated an impaired clearance of P. aeruginosa from the lung. Little or no neutrophil recruitment was observed in the airways of MyD88-/- mice following P. aeruginosa lung infection. This observation was associated with a reduced production of inflammatory mediators that affect neutrophil recruitment, including macrophage-inflammatory protein-2, tumor necrosis factor, and interleukin-1β in the airways of MyD88-/- mice. Similarly, MyD88-/- mice showed inhibited NF-κB activation in the lung following P. aeruginosa infection. Interestingly, P. aeruginosa infection induced a 7.5-fold increase of TLR2 mRNA expression in the lungs of MyD88+/+ mice. Furthermore, host responses to P. aeruginosa lung infection in TLR2-/- and TLR4 mutant mice were partially inhibited compared with the responses of respective control mice. Taken together, our results indicate that the MyD88-dependent pathway is essential for the development of early host responses to P. aeruginosa infection, leading to the clearance of this bacterium, and that TLR2 and TLR4 are involved in this process. Toll-like receptors (TLR) induce distinct patterns of host responses through myeloid differentiation factor 88 (MyD88)-dependent and/or -independent pathways, depending on the nature of the pathogen. Pseudomonas aeruginosa is a cause of serious lung infection in immunocompromised individuals and cystic fibrosis patients. The role of the TLR-MyD88 pathway in P. aeruginosa-induced lung infection in vivo was examined in this study. MyD88-/- mice demonstrated an impaired clearance of P. aeruginosa from the lung. Little or no neutrophil recruitment was observed in the airways of MyD88-/- mice following P. aeruginosa lung infection. This observation was associated with a reduced production of inflammatory mediators that affect neutrophil recruitment, including macrophage-inflammatory protein-2, tumor necrosis factor, and interleukin-1β in the airways of MyD88-/- mice. Similarly, MyD88-/- mice showed inhibited NF-κB activation in the lung following P. aeruginosa infection. Interestingly, P. aeruginosa infection induced a 7.5-fold increase of TLR2 mRNA expression in the lungs of MyD88+/+ mice. Furthermore, host responses to P. aeruginosa lung infection in TLR2-/- and TLR4 mutant mice were partially inhibited compared with the responses of respective control mice. Taken together, our results indicate that the MyD88-dependent pathway is essential for the development of early host responses to P. aeruginosa infection, leading to the clearance of this bacterium, and that TLR2 and TLR4 are involved in this process. Toll-like receptors (TLRs) 1The abbreviations used are: TLR, Toll-like receptors; MyD, myeloid differentiation; TRIF, Toll-interleukin-1 receptor domain-containing adaptor molecule-1; TRAM, TRIF-related adaptor molecule; TNF, tumor necrosis factor; IL, interleukin; BALF, bronchoalveolar lavage fluid; MPO, myeloperoxidase; CFU, colony-forming units; RT, reverse transcriptase; ELISA, enzyme-linked immunosorbent assay; Ifn, interferon; MIP, macrophage-inflammatory protein; IRF, Ifn-regulatory factor; RANTES, regulated on activation normal T cell expressed and secreted; LPS, lipopolysaccharide.1The abbreviations used are: TLR, Toll-like receptors; MyD, myeloid differentiation; TRIF, Toll-interleukin-1 receptor domain-containing adaptor molecule-1; TRAM, TRIF-related adaptor molecule; TNF, tumor necrosis factor; IL, interleukin; BALF, bronchoalveolar lavage fluid; MPO, myeloperoxidase; CFU, colony-forming units; RT, reverse transcriptase; ELISA, enzyme-linked immunosorbent assay; Ifn, interferon; MIP, macrophage-inflammatory protein; IRF, Ifn-regulatory factor; RANTES, regulated on activation normal T cell expressed and secreted; LPS, lipopolysaccharide. are a family of pattern recognition molecules that initiate intracellular signaling cascades on exposure to microbial molecules (1Barton G.M. Medzhitov R. Science. 2003; 300: 1524-1525Crossref PubMed Scopus (1053) Google Scholar). There are at least 10 TLRs (TLR1–TLR10) that induce signal transduction through adaptor proteins. Five TLR-associated adaptor proteins have been described previously (2Oshiumi H. Sasai M. Shida K. Fujita T. Matsumoto M. Seya T. J. Biol. Chem. 2003; 278: 49751-49762Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar, 3O'Neill L.A. Fitzgerald K.A. Bowie A.G. Trends Immunol. 2003; 24: 286-290Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar), including myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like (MAL) (also known as TIRAP), Toll-interleukin-1 receptor domain-containing adaptor molecule-1 (TICAM-1) (also know as TRIF), TICAM-2 (2Oshiumi H. Sasai M. Shida K. Fujita T. Matsumoto M. Seya T. J. Biol. Chem. 2003; 278: 49751-49762Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar), and TRIF-related adaptor molecule (TRAM). The adaptor usage by different TLRs provides a molecular basis for the differences in gene expression patterns induced by distinct TLRs (3O'Neill L.A. Fitzgerald K.A. Bowie A.G. Trends Immunol. 2003; 24: 286-290Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar). Given that MyD88 transduces a core set of TLR-induced signals (1Barton G.M. Medzhitov R. Science. 2003; 300: 1524-1525Crossref PubMed Scopus (1053) Google Scholar, 3O'Neill L.A. Fitzgerald K.A. Bowie A.G. Trends Immunol. 2003; 24: 286-290Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar), microbially induced immune responses can be divided broadly into the MyD88-dependent and MyD88-independent pathways. The MyD88-dependent pathway is essential for the host defense against microbial infections in vivo from organisms such as Staphylococcus aureus (4Takeuchi O. Hoshino K. Akira S. J. Immunol. 2000; 165: 5392-5396Crossref PubMed Scopus (904) Google Scholar) and Toxoplasma gondii (5Scanga C.A. Aliberti J. Jankovic D. Tilloy F. Bennouna S. Denkers E.Y. Medzhitov R. Sher A. J. Immunol. 2002; 168: 5997-6001Crossref PubMed Scopus (393) Google Scholar). In contrast, resistance to Mycobacterium tuberculosis infection is effected largely through MyD88-independent pathways (6Shi S. Nathan C. Schnappinger D. Drenkow J. Fuortes M. Block E. Ding A. Gingeras T.R. Schoolnik G. Akira S. Takeda K. Ehrt S. J. Exp. Med. 2003; 198: 987-997Crossref PubMed Scopus (123) Google Scholar, 7Sugawara I. Yamada H. Mizuno S. Takeda K. Akira S. Microbiol. Immunol. 2003; 47: 841-847Crossref PubMed Scopus (74) Google Scholar). In acute polymicrobial peritonitis, the effective antibacterial immune response occurs in the absence of MyD88 (8Weighardt H. Kaiser-Moore S. Vabulas R.M. Kirschning C.J. Wagner H. Holzmann B. J. Immunol. 2002; 169: 2823-2827Crossref PubMed Scopus (123) Google Scholar). In other cases, both MyD88-dependent and -independent mechanisms are involved. 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Respir. 2004; 5: PubMed Scopus Google Scholar). In expression of TLR4 to with impaired resistance to P. aeruginosa infection T. J. T. Nature. 2001; PubMed Scopus Google Scholar). In TLR2 and are involved in P. aeruginosa activation of (24Adamo R. Sokol S. Soong G. Gomez M. Prince A. Am. J. Respir. Cell Mol. Biol. 2004; 30: 627-634Crossref PubMed Scopus (213) Google Scholar), and TLR2 and TLR4 are involved in and activation by a of P. aeruginosa T.H. E. O. E. O. Akira S. G. T. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the TLR-MyD88 pathway to the effective host response to P. aeruginosa lung infection a of that mice showed or no neutrophil recruitment or production of the neutrophil TNF, and and an impaired to P. aeruginosa from the with the of TNF, and neutrophil and clearance demonstrated in an essential role for the MyD88-dependent pathway in the host defense against P. aeruginosa lung infection in The different immune responses in and TLR4 mutant mice that the host defense against P. aeruginosa lung infection of the MyD88-dependent mice to the and mice were by S. Akira O. T. Takeda K. Matsumoto M. H. M. K. Akira S. Immunity. Full Text Full Text PDF PubMed Scopus Google Scholar). mice were from MyD88-/- mice were with mice for and mice and mice were from the The were by the on in with the of the on with P. aeruginosa and of and aeruginosa from A. of is a from a cystic fibrosis S. Mol. Microbiol. 30: PubMed Scopus Google Scholar). were with or of P. or mice were by and was into the to from the lavage was by the lung with of tissue was for the of cytokines and for and for and tissue was in lung For CFU, 10 of the was on an and for at The was at for at The was at for of The was and in lung and as The was used for the was on an and for and were For the of cytokines and was at for at were used for The were in of and as to The were and the were in and and the were used for was used to the of neutrophils into the lungs of the mice as described previously T. J. Immunol. 1996; 198: PubMed Scopus Google Scholar). in were with of the and for The was by of The was at was a was from the lung tissue and reverse Specific for TLR2, and TLR4 were to the C.A. J. 1996; PubMed Scopus Google Scholar). was used as an were a to the and from mice were used as the are expressed as the increase to mice. of TNF, in the and were by TNF, and were as described previously R. J. Immunol. 2002; 169: PubMed Scopus Google Scholar) from NF-κB was used for the was by with in the of were on a 10 of was to a of with of and at for NF-κB was to was at for and by on a in were and to was by of to the that NF-κB was used for to and were used for for NF-κB proteins lungs were in and in for and were with and through of were with Harris to lung are as of the of was by with of and the or by an were at of P. aeruginosa in used mice to the role of MyD88 in the host defense against P. aeruginosa lung infection in MyD88+/+ and MyD88-/- mice were with of P. aeruginosa and lung tissue were for the of by MyD88+/+ mice are to P. aeruginosa can be in both the and lung tissue from MyD88-/- mice that MyD88-/- mice impaired clearance in with MyD88+/+ mice. Recruitment to the in that neutrophils are essential for the clearance of P. aeruginosa acute lung infection (15Cripps A.W. Dunkley M.L. Clancy R.L. Kyd J. Immunol. Cell Biol. 1995; 73: 418-424Crossref PubMed Google Scholar), the impaired clearance in MyD88-/- mice was by neutrophil MyD88+/+ and MyD88-/- mice were with P. aeruginosa or the and lung tissue were for In MyD88+/+ infection with P. aeruginosa for induced an of in the lung in the BALF, that at this neutrophils in were to the lung the of infection, a increase of was observed in both and lung tissue in MyD88+/+ mice a and in was observed in or lung tissue or of P. aeruginosa lung infection in the MyD88-/- mice a and an impaired neutrophil recruitment to the lung in MyD88-/- mice. This is by of the lung. tissue from MyD88-/- mice showed neutrophil of P. aeruginosa infection, compared with the neutrophil recruitment in MyD88+/+ mice P. aeruginosa-induced of TNF, and in in neutrophils have normal in vivo neutrophil recruitment to the has been to be normal in MyD88-/- mice polymicrobial infection (8Weighardt H. Kaiser-Moore S. Vabulas R.M. Kirschning C.J. Wagner H. Holzmann B. J. Immunol. 2002; 169: 2823-2827Crossref PubMed Scopus (123) Google Scholar). that the impaired neutrophil recruitment in the lungs of mice be by a in the production of neutrophil cytokines and chemokines that are for neutrophil in vivo were the direct neutrophil S. K. H. G. C. K. S. J. Am. J. 1996; PubMed Google Scholar, K.A. J. Immunol. 2000; PubMed Scopus Google Scholar) and and (17Wagner J.G. Roth R.A. Pharmacol. Rev. 2000; 52: 349-374PubMed Google Scholar). mRNA expression by lung tissue from MyD88+/+ and MyD88-/- mice of P. aeruginosa infection was used to A increase of mRNA expression was in MyD88+/+ mice. In contrast, was response in MyD88-/- mice production at the and lung tissue from MyD88+/+ and MyD88-/- mice or of P. aeruginosa lung infection were used to by P. aeruginosa infection induced a increase of in the and lung tissue in MyD88+/+ mice. In contrast, was production in MyD88-/- mice and of and were examined of essential in neutrophil recruitment to the lung in vivo (17Wagner J.G. Roth R.A. Pharmacol. Rev. 2000; 52: 349-374PubMed Google Scholar). In MyD88+/+ P. aeruginosa lung infection induced an production of in the lung tissue and in the In contrast, was response of or in lung tissue or from MyD88-/- mice and is that in P. aeruginosa-induced largely in the lung tissue the of was in the Given that and have been implicated in P. aeruginosa lung infection C. O. J. A. Hoiby N. Exp. Immunol. 2002; PubMed Scopus Google Scholar, T. Y. K. Y. S. K. Yamada Y. S. S. J. Med. Microbiol. 2000; PubMed Scopus Google Scholar), cytokines were examined in both MyD88+/+ and MyD88-/- mice. were for or with an of P. aeruginosa The and lung tissue were used to the of production of and by In to the response of neutrophil and TNF, was and response in both MyD88+/+ and MyD88-/- mice or of P. aeruginosa lung infection the role of MyD88 in P. aeruginosa-induced NF-κB lung tissue from P. or mice were used to for the of NF-κB activation by P. aeruginosa-induced NF-κB activation was in mice In contrast, P. aeruginosa-induced NF-κB activation was reduced in MyD88-/- mice. are with the of P. aeruginosa-induced mediator production in MyD88-/- mice as in 3 and TLR2, mRNA in the P. aeruginosa MyD88 is in TLR the of a P. aeruginosa-induced response in MyD88-/- mice that TLR have a role in P. aeruginosa-induced host P. aeruginosa infection in TLR2 and TLR4 lung tissue from P. MyD88+/+ and MyD88-/- mice was used to mRNA by were expressed as the increase to the in mice by the from as a in the of TLR2 expression in MyD88+/+ and MyD88-/- mice were Interestingly, P. aeruginosa infection induced a increase in TLR2 expression in MyD88+/+ mice in MyD88-/- mice the that TLR2 is involved in P. aeruginosa lung infection. in TLR4 in the lung was in MyD88+/+ and MyD88-/- mice TLR4 a role in P. aeruginosa-induced of TLR2 TLR4 mutant mice were tissue from or P. mice was to for TLR2 are expressed as the increase to the in mice. in P. aeruginosa infection on TLR2 an role for TLR4 in P. aeruginosa-induced TLR2 P. aeruginosa-induced in TLR4 the of TLR2 and TLR4 in the development of early immune responses in the lung following P. aeruginosa infection, TLR2-/- and TLR4 mutant mice as as control mice were with P. aeruginosa for were used to neutrophil and TLR2-/- mice showed a in neutrophil recruitment compared with mice a P. aeruginosa-induced and production was observed in TLR2-/- mice that TLR2 be a major in P. aeruginosa-induced Similarly, TLR4 mutant mice showed P. aeruginosa-induced production of and compared with mice with TLR4 mutant mice demonstrated a of neutrophil recruitment and and production on the nature of the microbial infection, the of the host defense including in the receptor signaling pathways, and the pattern of gene expression (10Pulendran B. Palucka K. Banchereau J. Science. 2001; 293: 253-256Crossref PubMed Scopus (396) Google Scholar, A.W. Dunkley M.L. Clancy R.L. Kyd J. Immunol. Cell Biol. 1995; 73: 418-424Crossref PubMed Google Scholar). The mechanisms of the host defense against P. aeruginosa lung infection in vivo The lung has a with the and has distinct to from microbial with immune mechanisms that are responsible for the of organisms R.M. Infect. Dis. 2003; PubMed Scopus Google Scholar, P. S. Immunol. Rev. 2000; PubMed Scopus Google Scholar). P. aeruginosa, a lung to have a with the lung J.R. Microbiol. Rev. 1996; PubMed Google Scholar). P. aeruginosa-induced lung is the major cause of in cystic fibrosis patients (11Koch C. Hoiby N. Lancet. 1993; 341: 1065-1069Abstract PubMed Scopus (364) Google Scholar) and for of the cause of in with pneumonia Brewer S. Wunderink R.G. Jones C.B. Leeper Jr., K.V. Chest. 1996; 109: 1019-1029Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). to the role of the TLR-MyD88 pathway in the host defense against P. aeruginosa lung infection. with a C.B. J. Immunol. 2004; PubMed Scopus Google Scholar), our results that the MyD88-dependent pathway is a of the initiation of P. aeruginosa-induced early immune responses in the leading to the clearance of this neutrophils play a major role in the clearance of P. aeruginosa from the the clearance of P. aeruginosa in MyD88-/- mice is by a recruitment of neutrophils into the Given that MyD88-/- neutrophils to have a normal (8Weighardt H. Kaiser-Moore S. Vabulas R.M. Kirschning C.J. Wagner H. Holzmann B. J. Immunol. 2002; 169: 2823-2827Crossref PubMed Scopus (123) Google Scholar), the of neutrophils into the airways is the of production of neutrophil in the lung of MyD88-/- mice as observed in this study. our results the in acute P. aeruginosa lung infection, MyD88 is for the early production of the cytokines and chemokines and TNF, are responsible for neutrophil recruitment and this the of the of MyD88-independent pathways such as the pathway in the P. aeruginosa-induced host in the of the infection. Several Ifn-regulatory factor cytokines and chemokines such as and 10 are induced by the pathway in response to Fitzgerald K.A. Mol. 2003; PubMed Scopus Google Scholar, K.A. A. E. B. J. Exp. Med. 2003; 198: PubMed Scopus Google Scholar). and 10 are P. aeruginosa infection K.A. D.J. Infect. Immun. PubMed Google Scholar). the role for the pathway in P. aeruginosa-induced lung infection study. Given the of MyD88 in TLR signaling (1Barton G.M. Medzhitov R. Science. 2003; 300: 1524-1525Crossref PubMed Scopus (1053) Google Scholar) and the of the between P. aeruginosa and TLR2 or TLR4 (24Adamo R. Sokol S. Soong G. Gomez M. Prince A. Am. J. Respir. Cell Mol. Biol. 2004; 30: 627-634Crossref PubMed Scopus (213) Google Scholar, T. J. T. Nature. 2001; PubMed Scopus Google Scholar, T.H. E. O. E. O. Akira S. G. T. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), immune responses to P. aeruginosa infection were examined in and TLR4 mutant with the of the of molecules as as TLRs in P. aeruginosa infection. the pattern of P. aeruginosa-induced immune responses in TLR2-/- or TLR4 mutant mice is different from that in MyD88-/- mice. results that TLR2 TLR4 as the responsible for P. immune response in the lung in This that such as (24Adamo R. Sokol S. Soong G. Gomez M. Prince A. Am. J. Respir. Cell Mol. Biol. 2004; 30: 627-634Crossref PubMed Scopus (213) Google Scholar, J. K. B. Sci. 2003; PubMed Scopus Google Scholar), or between different TLRs S. F. T. O. Takeda K. Akira S. J. Immunol. 2000; 165: PubMed Scopus Google Scholar) be involved. the increase of TLR2 expression in the lung P. aeruginosa infection and the of immune responses in TLR2-/- mice a role for TLR2 in P. aeruginosa-induced lung inflammation. This is with in G. B. Sokol S. R. Prince A. J. 2004; PubMed Scopus Google Scholar) that TLR2 is involved in the activation of and by a of P. aeruginosa that is to the T.H. E. O. E. O. Akira S. G. T. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, TLR2 is into an receptor in P. aeruginosa In TLR2 with and gangliotetraosylceramide have been to be involved in P. aeruginosa cell activation in (24Adamo R. Sokol S. Soong G. Gomez M. Prince A. Am. J. Respir. Cell Mol. Biol. 2004; 30: 627-634Crossref PubMed Scopus (213) Google Scholar). the of TLR4 mRNA was the of P. aeruginosa-induced neutrophil and production of and in TLR4 mutant mice a role for TLR4 in P. aeruginosa lung infection. the in MyD88-/- a P. aeruginosa-induced production of and was observed in TLR4 mutant mice. M.M. E. J. Immunol. 1983; Google Scholar, Microbiol. 1993; PubMed Google Scholar) have demonstrated P. aeruginosa-induced immune responses in mice. other TLRs in to TLR4 or between TLRs be involved in host responses to P. aeruginosa lung infection. The increase in TLR2 mRNA expression and the TLR4 mRNA in P. lungs that TLR2 and TLR4 have different P. aeruginosa infection. is that the of TLR2 increase the infection the 7.5-fold increase of TLR2 mRNA in the lungs of P. mice. The P. aeruginosa-induced increase of TLR2 mRNA was observed in TLR4 mutant mice. This that P. aeruginosa TLR2 through activation of is that TLR4 is associated with exposure to LPS, leading to a of to J. Immunol. 2000; PubMed Scopus Google Scholar). is that TLR4 a major role the early of P. aeruginosa infection, TLR2 play a role as the infection has been that MyD88 transduces cell surface signals to factor gene including and (1Barton G.M. Medzhitov R. Science. 2003; 300: 1524-1525Crossref PubMed Scopus (1053) Google Scholar). P. aeruginosa-induced NF-κB activation has been previously E. R. S. Prince A. J. PubMed Google Scholar) and was in our in the lung tissue an The production of and in MyD88-/- mice is by the of signaling from TLRs to NF-κB in P. aeruginosa-induced NF-κB activation in the lung was reduced in MyD88-/- mice. Interestingly, and can be regulated in a K.A. A. E. B. J. Exp. Med. 2003; 198: PubMed Scopus Google Scholar), MyD88-/- mice showed an in expression of both mRNA and and 10 in and are regulated through the pathway TLR activation K.A. A. E. B. J. Exp. Med. 2003; 198: PubMed Scopus Google Scholar, T. O. Fujita T. J. S. Hoshino K. Akira S. J. Immunol. 2001; PubMed Scopus Google Scholar). In contrast, is no the of an in the the a NF-κB U. A. B. J. Immunol. 1993; Google Scholar), production to be the NF-κB and production has no on expression M. K. M. K. M. J. Immunol. 2003; PubMed Scopus Google Scholar). MyD88 production through through MyD88-dependent production be to the production of and and are to expression K.A. J. Immunol. 2000; PubMed Scopus Google Scholar, G. Am. J. 2003; PubMed Scopus Google Scholar). the role for MyD88 in the host defense against P. aeruginosa lung infection is to on the of P. aeruginosa-induced mediators in the such as TNF, and In our results that the MyD88-dependent pathway an essential role in P. aeruginosa-induced early immune including and production and neutrophil recruitment and MyD88-dependent including TLR2 and be involved in the host defense against P. aeruginosa lung infection. for in the and for in the

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