title: Injury primes the innate immune system for enhanced Toll-like receptor reactivity.
abstract: Severe injury causes a dramatic host response that disrupts immune homeostasis and predisposes the injured host to opportunistic infections. Because Toll-like receptors (TLRs) recognize conserved microbial Ags and endogenous danger signals that may be triggered by injury, we wanted to determine how injury influences TLR responses. Using an in vivo injury model, we demonstrate that injury significantly increased TLR2- and TLR4-induced IL-1beta, IL-6, and TNF-alpha production by spleen cells. This influence of injury on TLR reactivity was observed as early as 1 day after injury and persisted for at least 7 days. The outcome of similar studies performed using TLR4-mutant C57BL/10ScN/Cr mice revealed that TLR2 responses remained primed, thus suggesting that injury-induced priming can occur independently of endogenous TLR4 signaling. Increased TLR4 reactivity was also observed in vivo, because LPS-challenged injured mice demonstrated significantly higher cytokine expression levels in the lung, liver, spleen, and plasma. Macrophages and dendritic cells were the major source of these cytokines as judged by intracellular cytokine staining. Moreover, ex vivo studies using enriched macrophage and dendritic cell populations confirmed that T cells did not contribute to the enhanced TLR2 and TLR4 responses. The results of flow cytometry studies using TLR2- and TLR4-MD-2-specific Abs indicated that injury did not markedly alter cell surface TLR2 or TLR4-MD-2 expression. Taken together, these findings establish that injury primes the innate immune system for enhanced TLR2- and TLR4-mediated responses and provides evidence to suggest that augmented TLR reactivity might contribute to the development of heightened systemic inflammation following severe injury.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hugh M
authors.initials: HM
authors.lastname: Paterson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Murphy
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Purcell
authors.forename: Odhran
authors.initials: O
authors.lastname: Shelley
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Kriynovich
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
authors.forename: John A
authors.initials: JA
authors.lastname: Mannick
authors.forename: James A
authors.initials: JA
authors.lastname: Lederer
mesh_terms: D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D002056:Burns / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004195:Disease Models, Animal; D007107:Immune System / Q000166:cytology / Q000276:immunology* / Q000293:injuries* / Q000378:metabolism; D007113:Immunity, Innate; D007375:Interleukin-1 / Q000096:biosynthesis; D051218:Lymphocyte Antigen 96; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000950:Antigens, Ly; D016207:Cytokines; D007375:Interleukin-1; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha