Resident macrophages of the lung and liver: The guardians of our tissues

Abstract

Resident macrophages play a unique role in the maintenance of tissue function. As phagocytes, they are an essential first line defenders against pathogens and much of the initial characterization of these cells was focused on their interaction with viral and bacterial pathogens. However, these cells are increasingly recognized as contributing to more than just host defense. Through cytokine production, receptor engagement and gap junction communication resident macrophages tune tissue inflammatory tone, influence adaptive immune cell phenotype and regulate tissue structure and function. This review highlights resident macrophages in the liver and lung as they hold unique roles in the maintenance of the interface between the circulatory system and the external environment. As such, we detail the developmental origin of these cells, their contribution to host defense and the array of tools these cells use to regulate tissue homeostasis.

Keywords: Kupffer cells; alveolar macrophages; homeostasis; inflammation; interstitial macrophages; liver; lung; macrophages.

Figure 1

Tissue seeding. Signals and transcription factors involved in seeding of well-known tissue-resident macrophages from fetal liver p-Macs. Migration from the liver occurs in a CX3CR1 dependent manner. In the skin IL-34 and TGF-β induce the transcription factors RUNX3 and ID2 to generate Langerhans cells. In the lung GM-CSF induces the transcription factors PPARγ, BACH2, and CEBPβ to produce alveolar macrophages. In the brain/central nervous system, microglia are generated in response to the induction of the transcription factor SALL1. Red pulp macrophages in the spleen are produced in response to Heme and the transcription factor SPIC. Finally, in the liver Kupffer cells are generated in response to TGF-β and the transcription factor ID3.

Figure 2

Heterogeneity of hepatic macrophages. In mice, liver-resident macrophages known as Kupffer cells (KCs) are classically defined by positive expression of CD11b, CD68, F4/80, Clec4f and negativity for Ly6C. They are located in liver sinusoids, where they adhere to liver sinusoid endothelial cells (LSECs). KCs thanks to their particular location remain in close contact with blood stream, which allows them to detect a variety of antigens. During homeostasis the pool of KCs is being replenished by cell renewal. During acute or chronic liver injury KCs get activated and secrete cytokines and chemokines that can recruit other immune cells from the circulating blood. Some of the secreted cytokines or chemokines thanks to fenestrae present between LSECs can reach liver parenchyma and directly affect hepatocytes and other immune cells located there. Haptic injury and/or chronic inflammation increases apoptotic rate of KCs and when self-renewal does not suffice to maintain their population, we can observe increased recruitment of monocytes, characterized by positivity for CD11b and Ly6C, with concomitant negativity to CD68, F4/80 and Clec4f. Once they enter parenchyma through endothelial fenestration, they differentiate into KC-like cells called monocyte-derived macrophages (MoMFs), that resemble the phenotype and function of KCs. These highly pro-inflammatory cells can be recognized by positivity for some markers typical for both KCs and monocytes: CD11b, F4/80 and Ly6C, while they remain negative for Clec4f. They also repopulate hepatic macrophages niche after increased death of KCs due to injury.

Figure 3

Macrophages in the lung. Location of tissue-resident macrophages in the lung and their distinguishing surface markers at steady-state. Alveolar macrophages located within the alveolar lumen express high levels of SiglecF and CD11c, and low levels of CD11b. Interstitial macrophages located in the alveolar interstitium express low levels of Lyve1, high levels of MHCII, and are CD206 negative. Interstitial macrophages located in the bronchial interstitium express high levels of Lyve1, low levels of MHCII, and are CD206 positive. Both interstitial macrophage subsets express low levels of CD11c and high levels of CD11b.

Figure 4

Homeostasis and inflammation in the lung. Roles of tissue-resident macrophage subsets in the lung during homeostasis and inflammation. Homeostasis: Alveolar macrophage maintenance relies on autocrine TGF-β and epithelial cell release of GM-CSF. Interstitial macrophages constitutively release IL-10. Inflammation: Activated alveolar macrophages release cytokines to recruit other immune cells and promote an inflammatory response. Interstitial macrophages upregulate their release of IL-10.All figures were created with BioRender.com.