Toll-like receptors, Notch ligands, and cytokines drive the chronicity of lung inflammation

Abstract

Current dogma supports the concept that the expression of a disease-inducing signature cytokine phenotype is important to the maintenance stage of chronic lung disorders. This cytokine phenotype has been characterized as a polarization toward type 2 cytokines, which are profibrotic and immunoregulatory. The biology of this latter activity could mechanistically explain pathogen-induced exacerbation of chronic lung inflammation, as a skewed cytokine profile in the lung alters dendritic cell function, activates fibroblasts, and facilitates a subsequent "second hit" by an infectious pathogen. In this setting, cytokine biology is also linked to Toll-like receptors (TLRs) in the maintenance of lung immunity, as the activity of this receptor-ligand system by both leukocytes and stromal cells is likely an important component of disease chronicity. The participation of dendritic cells via TLRs in chronic lung disease could facilitate communication circuits established between antigen-presenting cells and lymphocytes. Data suggest that TLR activation via myeloid differentiation factor 88 adaptor protein leads to the induction of a Notch ligand known as Delta-like-4 on dendritic cells that activate the Notch receptor on T cells, promoting a helper T-cell type 1 cytokine response. It is likely that the evolution of host defense signals designed to recognize patterns emitted from a hostile microbial environment may now be superimposed on adaptive immunity and provide the underpinning to support the maintenance of chronic lung disease.

Figure 1.

Host response during chronic pulmonary disease. Evolution of chronic lung inflammation driven by type 2 cytokines, which induce a susceptible state for lung tissue to become infected with a respiratory virus. DC = dendritic cells.

Figure 2.

Hematoxylin-and-eosin–stained sections showing the progression of chronic lung response and kinetic assessment of cytokine, collagen, and cellular components 4, 8, and 16 days after lung challenge with Schistosoma mansoni egg antigen. Mφ = macrophages.

Figure 3.

Murine herpesvirus strain 68 preferentially infects immature dendritic cells (A) and not mature dendritic cells (B). Data demonstrate that immature bone marrow–derived dendritic cells contain significant viral titers, whereas LPS-treated dendritic cells driven to maturity do not have a significant increase in viral titers relative to mock control.

Figure 4.

Hematoxylin-and-eosin (H&E)–stained sections of lung lesions from animals with developing type 2 immune granulomas: (A and B) wild-type (WT) mice and (C and D) myeloid differentiation factor 88 (MyD88)^−/− mice. A significant increase in size and cellularity is associated with the MyD88^−/− mice. Original magnification: (A and C) ×10; (B and D) ×40.

Figure 5.

Hematoxyoin-and-eosin (H&E)–stained sections of lung lesions from animals with developing type 2 immune responses: (A and B) wild-type (WT) mice and (C and D) Toll-like receptor 9 (TLR9)^−/− mice. Increased cellularity and the presence of stromal cell proliferative foci are demonstrated in the TLR9^−/− mice. Original magnification: (A and C) ×10; (B and D) ×40.

Figure 6.

Increase in lymphocyte-derived IL-5 and IL-13 assessed from T cells recovered from lung lymph nodes of animals with developing type 2 granulomas treated in vivo with antibodies to the Notch ligand Delta-like 4 and stimulated in vitro with schistosome egg antigen (SEA).