Contribution of alternatively activated macrophages to allergic lung inflammation: a tale of mice and men

Abstract

The concept that macrophages play an active role in inflammatory responses began its development in the late 1800s with the now iconic studies by Elie Metchnikoff using starfish larvae and Daphnia [reviewed in Kaufmann SHE: Nat Immunol 2008;9:705-712 and Cavaillon JM: J Leukoc Biol 2011;90:413-424]. Based on his observation of the phagocyte response to a foreign body (rose thorn) and yeast, he proposed that phagocytes acted in host defense and were active participants in the inflammatory process. Flash forward more than 100 years and we find that these basic tenets hold true. However, it is now appreciated that macrophages come in many different flavors and can adopt a variety of nuanced phenotypes depending on the tissue environment in which the macrophage is found. In this brief review, we discuss the role of one type of macrophage termed the alternatively activated macrophage (AAM), also known as the M2 type of macrophage, in regulating allergic lung inflammation and asthma. Recent studies using mouse models of allergic lung inflammation and samples from human asthma patients contribute to the emerging concept that AAMs are not just bystanders of the interleukin (IL)-4- and IL-13-rich environment found in allergic asthma but are also active players in orchestrating allergic lung disease.

Fig. 1

Possible roles for AAMs in asthma initiation and exacerbation. a Initiation. In step 1, molecular patterns found in pathogens (PAMPS) or allergens (AAMPS) stimulate PRRs expressed on lung epithelial cells and alveolar macrophages. These cells then make cytokines, including IL-25, IL-33 and TSLP, that stimulate cells of the innate immune system. These cytokines can activate dendritic cells (DC) and stimulate granuloctyes (mast cells and basophils) and innate lymphoid cells (not shown) to produce IL-4 or IL-13. IL-4 or IL-13 in combination with IL-33 drive AAM differentiation. In step 2, activated dendritic cells migrate to the draining lymph node (LN) and with the help of an IL-4-producing cell such as a basophil stimulate naive CD4+ T cells to become TH2 effectors or memory cells. In step 3, TH2 effectors migrate to the site of inflammation producing high levels of IL-4, IL-5 and IL-13. These cytokines mediate mucus secretion, AHR, chemokine production, eosinophilic infiltration and further AAM differentiation. b Exacerbation. In step 1, PAMPS or AAMPS stimulate PRRs expressed on lung epithelial cells and alveolar macrophages, leading to production of IL-25, IL-33 and TSLP. These cytokines stimulate granuloctyes (mast cells, basophils, eosinophils) and innate lymphoid cells (not shown) to produce IL-4 or IL-13. IL-4 or IL-13 in combination with IL-33 drive additional AAM differentiation. In step 2, lung epithelial cells and AAMs produce chemokines and other factors that recruit more inflammatory cells from the blood including eosinophils and monocytes. Increased numbers of macrophages in the lung tissue may also come from proliferation of interstitial macrophages as has been noted during parasitic infections [86]. In step 3, allergen-specific memory TH2 cells migrate to the site of inflammation, producing high levels of IL-4, IL-5 and IL-13. These cytokines mediate mucus secretion, AHR, chemokine production, eosinophilic infiltration and further AAM differentiation, setting up a positive amplification loop. MΦ = Macrophage.