Journal of Respiratory Medicine
Open Access

Bronchoalveolar; Pulmonary; Immunity; Monocytes

Introduction

Macrophages are blood monocyte-derived scavenger cells that play an important role in innate immunity and steady-state homeostasis [1]. Pulmonary macrophages are highly heterogeneous due to their anatomical location, specialized functions, and activation state [2, 3]. At least three types of macrophages have been identified in the lung, including alveolar macrophages (AM), interstitial macrophages (IM), and intravascular/limbic vascular macrophages, which differ in location and function [4]. In general, AM is thought to act to clear particles and microorganisms within the alveoli, and IM is thought to act in regulating tissue fibrosis, inflammation, and antigen presentation [5]. Perivascular macrophages appear to function by crosstalk between antigen-presenting cells in the lung stroma and recruit neutrophils or myeloid cell. The existence of subsets of pulmonary macrophages with distinct functional properties requires additional analyzes to better understand their contribution to lung disease pathogenesis.

Macrophages were recognized more than a century before Elie Metchnikoff first described phagocytosis and defined the role of these cells in inflammation in the 1880s, but monocyte/macrophage heterogeneity Questions remain about [6]. This is because macrophage classification is largely based on in vitro experiments and does not address the effects of the tissue microenvironment in which monocytes/macrophages live. For example, alveolar macrophages are unable to develop resistance to endotoxin (LPS) at concentrations induced by mononuclear phagocytes or macrophages in other tissue compartments such as the peritoneal cavity, bone marrow, and spleen. This difference is likely due to the rich GM-CSF microenvironment in the lung [7]. Moreover, species-specific responses appear to reside in the expression of functional genes and homologous proteins, as well as unique markers of macrophage populations located in different tissues and hosts that contribute to the variability of the macrophage classification scheme.

Allergens such as house dust mites can cause apoptotic epithelial cell death and trigger the synthesis of IL-4 and IL-13 from mast cells and innate lymphoid type 2 cells (ILC2) [8, 9]. These events lead to the production of insulin-like growth factor 1 from Aφ, which facilitates the uptake of macrophage-derived anti-inflammatory microvesicles by the airway epithelium. Bourdonnet et al. reported that Aφ, a suppressor of cytokine signaling, can secrete SOCS1 and -3 into exosomes and microparticles, respectively, for uptake by alveolar epithelial cells and subsequent inhibition of STAT activation [10]. In particular, airway epithelial cells can use her PGE2 as a signal to induce her SOCS3 release from Aφ to dampen endogenous inflammatory responses in LPS inflammation models. Contact-dependent communication between Aφ and alveolar epithelium has also been described to regulate immunity through gap junction-like connections and calcium wave propagation [11]. The result of this intercellular communication was immunosuppression [12]. The binding of CD200R and TGF-βR expressed by Aφ to their ligands (CD200 and TGF-β, respectively) present on the plasma membrane of epithelial cells is a negative regulator of Aφ activation [13].

Another mechanism by which Arφ limits inflammation is by promoting regulatory T cell (Treg) responses. M2-like macrophages activated by cancer cells induce activated Treg cells from CD4+CD25- T cells in vitro. Interestingly, the authors also demonstrated a positive feedback loop in which activated Tregs skewed monocyte differentiation toward an M2-like phenotype [14]. Lung tissue-resident macrophages (Siglec F+ CD11c+ AutoFluorescenthi, presumably Aφs) isolated from mice are pulsed with ovalbumin when co-cultured with antigen-specific CD4 T cells to generate Foxp3+ Treg cells. Both TGF-β and retinoic acid were required for Treg cell induction. Thus, migration of antigen-pulsed tissue macrophages into the airways prevented the development of asthmatic pneumonitis after subsequent provocation with ovalbumin. However, other allergens such as Dermatophagoides pteronyssinus, Aspergillus fumigatus, or extracts from cat dander did not induce he Tregs due to signaling through proteases and her TLRs. Macrophages can also induce Tregs through an indirect pathway. Indeed, interleukin-6, a soluble mediator commonly associated with inflammation and elevated in people with severe respiratory infections, is important in promoting resolution of the host response to respiratory viral infections and limiting disease. Early but not late IL-6 signaling is required for resolution of immunopathology induced by respiratory syncytial virus.

Once inflammation is under control, tissue repair must occur to restore normal tissue architecture. In the lung, epithelial cells are the main cells damaged by infection and inflammation [15]. As long as the injury persists, the pro-inflammatory signals continue, further damaging the epithelium. Repair processes can therefore be considered an integral part of the resolution of inflammation.

The environment created by tissue damage control may favor pathogen persistence in the respiratory tract. Indeed, the immunosuppressive properties of Aφ in the process of tissue damage control are thought to be key leading to immune evasion. Bypassing immune surveillance is a key parameter leading to pathogen persistence. These bacteria persist in the lower respiratory tract by surviving within Aφ. In vitro studies revealed that S. aureus persists and replicates within the mouse Aφ cell line [16]. We have previously stated that among the mediators used by Aφ to control tissue damage, PGE2 is produced after efferocytosis and exerts anti-inflammatory effects. PGE2 is known to suppress natural killer cell activity by increasing cellular cyclic adenosine monophosphate and downregulating MHC class II expression in dendritic cells, reducing antigen presentation. increase. Recently, it has been shown that the anti-inflammatory effects of PGE2 in the lung are mediated exclusively through prostaglandin E receptor 4 (EP4). Thus, pathogens appear to be able to utilize PGE2 [17, 18]. In fact, PGE2 can block Aφ-induced bacterial killing by inhibiting her NADPH oxidase. In M. tuberculosis-infected macrophages, her PGE2 generated by TLR2 stimulation/p38 MAPK phosphorylation triggers her EP4 to increase PGE2 levels [19]. PGE2 then provides protection against necrosis via EP2. Host production of PGE2 is a protective mechanism against Mycobacterium tuberculosis by inhibiting IFN type I in macrophages and inducing apoptosis. Similarly, influenza virus induces PGE2 to suppress type I IFNs, thereby weakening innate immunity [20]. Taken together, the pathogen appears to have evolved mechanisms that induce her PGE2 production by macrophages to suppress inflammation and better survive within the host. A recent studies show that dendritic cells and macrophages that develop in the lung after resolution of severe infection acquire tolerogenicity that contributes to persistent immunosuppression and susceptibility to secondary infections.

Conclusion

Taken together, these studies suggest that Aφ is involved in (i) limiting lung tissue damage from potentially harmless stimuli, (ii) reducing immune surveillance, and (iii) harboring pathogens, thereby It has been shown to play a central role in pulmonary disease resistance. Pathogen persistence in the respiratory tract is a major concern, especially for diseases such as tuberculosis. In fact, the balance between eliminating pathogens and maintaining tissue integrity is the sword of Damocles for susceptible patients. , can offer treatment options. An important area that needs further investigation is to distinguish between the role of resident and recruited macrophages in the lung environment. It is of great interest how recruited macrophages interfere with various functions of resident Aφ to maintain lung homeostasis.

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