Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

/pdf/exploring-the-full-spectrum-of-macrophage-activation-b5rnrcgcen.pdf

Exploring the full spectrum of macrophage activation.

Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive airway diseases that involve chronic inflammation of the respiratory tract, but the type of inflammation is markedly different between these diseases, with different patterns of inflammatory cells and mediators being involved As described in this Review, these inflammatory profiles are largely determined by the involvement of different immune cells, which orchestrate the recruitment and activation of inflammatory cells that drive the distinct patterns of structural changes in these diseases However, it is now becoming clear that the distinction between these diseases becomes blurred in patients with severe asthma, in asthmatic subjects who smoke and during acute exacerbations This has important implications for the development of new therapies

Immunology of asthma and chronic obstructive pulmonary disease

The key role of interleukin-17 (IL-17) and T helper 17 (T(H)17) cells in tissue inflammation, autoimmunity and host defence led to the experimental targeting of these molecules in mouse models of diseases as well as in clinical settings. Moreover, the demonstration that IL-17 and T(H)17 cells contribute to local and systemic aspects of disease pathogenesis, as well as the finding that the IL-17-T(H)17 cell pathway is regulated by IL-23, prompted the identification of inhibitors. These inhibitors include biotechnology products that target IL-23 as well as the leading member of the IL-17 family, IL-17A, and one of its receptors, IL-17 receptor A. Several clinical trials of these inhibitors are underway, and positive results have been obtained in psoriasis, rheumatoid arthritis and ankylosing spondylitis. This Review focuses on the current knowledge of the IL-17-T(H)17 cell pathway to better understand the positive as well as potential negative consequences of targeting them.

Targeting IL-17 and TH17 cells in chronic inflammation.

Pulmonary fibrosis is a highly heterogeneous and lethal pathological process with limited therapeutic options. Although research on the pathogenesis of pulmonary fibrosis has frequently focused on the mechanisms that regulate the proliferation, activation, and differentiation of collagen-secreting myofibroblasts, recent studies have identified new pathogenic mechanisms that are critically involved in the initiation and progression of fibrosis in a variety of settings. A more detailed and integrated understanding of the cellular and molecular mechanisms of pulmonary fibrosis could help pave the way for effective therapeutics for this devastating and complex disease.

/pdf/integrating-mechanisms-of-pulmonary-fibrosis-1qxhh2yukr.pdf

Integrating mechanisms of pulmonary fibrosis

The IL-23/Th17 Axis in the Immunopathogenesis of Psoriasis

γδ T cells: an important source of IL-17

Inflammation-induced pulmonary fibrosis (PF) leads to irreversible loss of lung function and is a predictor of mortality in numerous lung diseases. Why some subjects with lung inflammation but not others develop PF is unclear. In a mouse model of hypersensitivity pneumonitis that progresses to lung fibrosis upon repeated exposure to the ubiquitous microorganism Bacillus subtilis, γδ T cells expand in the lung and inhibit collagen deposition. We show that a subset of these γδ cells represents the predominant source of the Th17 cytokine IL-22 in this model. Preventing expression of IL-22, either by mutating the aryl hydrocarbon receptor (AhR) or inhibiting AhR signaling, accelerated lung fibrosis. Direct blockade of IL-22 also enhanced collagen deposition in the lung, whereas administration of recombinant IL-22 inhibited lung fibrosis. Moreover, the presence of protective γδ T cells and IL-22 diminished recruitment of CD4+ T cells to lung. These data reveal a protective pathway that involves the inhibition of αβ T cells by regulatory IL-22–secreting γδ T cells.

/pdf/gd-t-cells-protect-against-lung-fibrosis-via-il-22-1yl0nxed0t.pdf

γδ T cells protect against lung fibrosis via IL-22

Hypersensitivity pneumonitis is an environmental lung disease characterized by a diffuse mononuclear cell infiltrate in the lung that can progress to pulmonary fibrosis with chronic exposure to an inhaled Ag Using a well-established murine model of hypersensitivity pneumonitis, we repeatedly exposed C57BL/6 mice to Saccharopolyspora rectivirgula to investigate whether T cells are required for lung fibrosis In the absence of αβ T cells, TCRβ−/− mice exposed to S rectivirgula for 4 wk had markedly decreased mononuclear infiltrates and collagen deposition in the lung compared with wild-type C57BL/6 mice In contrast to CD8+ T cells, adoptive transfer of CD4+ T cells reconstituted the S rectivirgula-induced inflammatory and fibrotic response, suggesting that the CD4+ T cell represents the critical αβ T cell subset Cytokine analysis of lung homogenates at various time points after S rectivirgula exposure failed to identify a predominant Th1 or Th2 phenotype Conversely, IL-17 was found in the lung at increasing concentrations with continued exposure to S rectivirgula Intracellular cytokine staining revealed that 14% of CD4+ T cells from the lung of mice treated with S rectivirgula expressed IL-17A In the absence of IL-17 receptor signaling, Il17ra−/− mice had significantly decreased lung inflammation and fibrosis compared with wild-type C57BL/6 mice These data are the first to demonstrate an important role for Th17-polarized CD4+ T lymphocytes in the immune response directed against S rectivirgula in this murine model of hypersensitivity pneumonitis and pulmonary fibrosis

Th17-Polarized Immune Response in a Murine Model of Hypersensitivity Pneumonitis and Lung Fibrosis

Rationale: Within the lungs of patients with severe emphysema, inflammation continues despite smoking cessation. Foci of T lymphocytes in the small airways of patients with emphysema have been associated with disease severity. Whether these T cells play an importantroleinthiscontinuedinflammatoryresponseisunknown. Objective: The aim of this study was to determine if T cells recruited to the lungs of subjects with severe emphysema contain oligoclonal T-cell populations, suggesting their accumulation in response to antigenic stimuli. Methods: Lung T-cell receptor (TCR) V repertoire from eight patientswith severe emphysema andsix control subjects was evaluated at the time of tissue procurement (ex vivo) and after 2 weeks of culture with interleukin 2 (in vitro). Junctional region nucleotidesequencingofexpandedTCR-Vsubsetswasperformed. Results: No significantly expanded TCR-V subsets were identified in ex vivo samples. However, T cells grew from all emphysema (n 8) butfromonlyoneofthecontrollungsamples(n6)whenexposed to interleukin 2 (p 0.0013). Within the cultured cells, seven major CD4-expressingTCR-Vsubsetexpansionswereidentifiedfromfive of the patients with emphysema. These expansions were composed ofoligoclonalpopulationsofTcellsthathadalreadybeenexpanded in vivo. Conclusion: Severe emphysema is associated with inflammationinvolvingTlymphocytesthatarecomposedofoligoclonalCD4 T cells. These T cells are accumulating in the lung secondary to conventional antigenic stimulation and are likely involved in the persistent pulmonary inflammation characteristic of severe emphysema.

/pdf/oligoclonal-cd4-t-cells-in-the-lungs-of-patients-with-severe-2gyd4u3rlr.pdf

Oligoclonal CD4+ T cells in the lungs of patients with severe emphysema.

Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by a diffuse mononuclear cell infiltrate in the lung that can progress to pulmonary fibrosis with chronic exposure to an inhaled Ag. We previously reported that C57BL/6 mice repeatedly exposed to the ubiquitous microorganism Bacillus subtilis develop mononuclear infiltrates in the lung that contain Vγ6/Vδ1+ γδ T cells. In the absence of this T cell subset, mice treated with B. subtilis had significantly increased collagen deposition in the lung, suggesting a regulatory role for Vγ6/Vδ1+ γδ T cells. To further investigate the role of Vγ6/Vδ1+ γδ T cells in B. subtilis-induced lung fibrosis, we exposed transgenic Vγ6/Vδ1 mice to this microorganism and found decreased collagen content in the lung compared with wild-type C57BL/6 mice. Cytokine analysis of lung homogenates from wild-type C57BL/6 mice demonstrated increased IL-17A concentrations with repeated exposure to B. subtilis. In the absence of IL-17 receptor signaling, IL-17ra−/− mice had delayed clearance of B. subtilis with increased lung inflammation and fibrosis. Although IL-17A was predominantly expressed by Vγ6/Vδ1+ T cells, a compensatory increase in IL-17A expression by CD4+ T cells was seen in the absence of γδ T cells that resulted in similar levels of IL-17A in the lungs of TCRδ−/− and wild-type C57BL/6 mice. In combination, our data suggest an important role for IL-17A-expressing T lymphocytes, both γδ and αβ T cells, in eliminating this microorganism that prevents excessive inflammation and eventual lung fibrosis in this murine model of B. subtilis-induced hypersensitivity pneumonitis.

Philip L. Simonian

Papers

γδ T cells: an important source of IL-17

γδ T cells protect against lung fibrosis via IL-22

Th17-Polarized Immune Response in a Murine Model of Hypersensitivity Pneumonitis and Lung Fibrosis

Oligoclonal CD4+ T cells in the lungs of patients with severe emphysema.

IL-17A-Expressing T Cells Are Essential for Bacterial Clearance in a Murine Model of Hypersensitivity Pneumonitis