Flagellin treatment prevents increased susceptibility to systemic bacterial infection after injury by inhibiting anti-inflammatory IL-10+ IL-12- neutrophil polarization.
Severe trauma renders patients susceptible to infection. In sepsis, defective bacterial clearance has been linked to specific deviations in the innate immune response. We hypothesized that innate immune modulations observed during sepsis also contribute to increased bacterial susceptibility after severe trauma. A well-established murine model of burn injury, used to replicate infection following trauma, showed that wound inoculation with P. aeruginosa quickly spreads systemically. The systemic IL-10/IL-12 axis was skewed after burn injury with infection as indicated by a significant elevation in serum IL-10 and polarization of neutrophils into an anti-inflammatory ("N2"; IL-10(+) IL-12(-)) phenotype. Infection with an attenuated P. aeruginosa strain (ΔCyaB) was cleared better than the wildtype strain and was associated with an increased pro-inflammatory neutrophil ("N1"; IL-10(-)IL-12(+)) response in burn mice. This suggests that neutrophil polarization influences bacterial clearance after burn injury. Administration of a TLR5 agonist, flagellin, after burn injury restored the neutrophil response towards a N1 phenotype resulting in an increased clearance of wildtype P. aeruginosa after wound inoculation. This study details specific alterations in innate cell populations after burn injury that contribute to increased susceptibility to bacterial infection. In addition, for the first time, it identifies neutrophil polarization as a therapeutic target for the reversal of bacterial susceptibility after injury.
North Carolina Jaycee Burn Center, University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina, United States of America.
Crystal J
CJ
Neely
North Carolina Jaycee Burn Center, University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina, United States of America.
Laurel B
LB
Kartchner
North Carolina Jaycee Burn Center, University of North Carolina, Department of Surgery, Chapel Hill, North Carolina, United States of America.
April E
AE
Mendoza
North Carolina Jaycee Burn Center, University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina, United States of America.
Brandon M
BM
Linz
University of Arizona, Department of Immunobiology, Tucson, Arizona, United States of America.
Jeffrey A
JA
Frelinger
University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina, United States of America.
Matthew C
MC
Wolfgang
North Carolina Jaycee Burn Center, University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina, United States of America ; North Carolina Jaycee Burn Center, University of North Carolina, Department of Surgery, Chapel Hill, North Carolina, United States of America.
Robert
R
Maile
North Carolina Jaycee Burn Center, University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina, United States of America ; North Carolina Jaycee Burn Center, University of North Carolina, Department of Surgery, Chapel Hill, North Carolina, United States of America.
Bruce A
BA
Cairns
D000818:Animals; D002056:Burns / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D016764:Cell Polarity; D005260:Female; D005408:Flagellin / Q000494:pharmacology* / Q000627:therapeutic use; D007113:Immunity, Innate; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D011552:Pseudomonas Infections / Q000209:etiology / Q000517:prevention & control*; D018805:Sepsis / Q000209:etiology / Q000517:prevention & control*; D051193:Toll-Like Receptors / Q000378:metabolism
C556062:IL10 protein, mouse; D007155:Immunologic Factors; D051193:Toll-Like Receptors; D005408:Flagellin; D016753:Interleukin-10; D018664:Interleukin-12