Protection against influenza-induced Acute Lung Injury (ALI) by enhanced induction of M2a macrophages: possible role of PPARγ/RXR ligands in IL-4-induced M2a macrophage differentiation

Abstract

Many respiratory viruses cause lung damage that may evolve into acute lung injury (ALI), a cytokine storm, acute respiratory distress syndrome, and ultimately, death. Peroxisome proliferator activated receptor gamma (PPARγ), a member of the nuclear hormone receptor (NHR) family of transcription factors, regulates transcription by forming heterodimers with another NHR family member, Retinoid X Receptor (RXR). Each component of the heterodimer binds specific ligands that modify transcriptional capacity of the entire heterodimer by recruiting different co-activators/co-repressors. However, the role of PPARγ/RXR ligands in the context of influenza infection is not well understood. PPARγ is associated with macrophage differentiation to an anti-inflammatory M2 state. We show that mice lacking the IL-4Rα receptor, required for M2a macrophage differentiation, are more susceptible to mouse-adapted influenza (A/PR/8/34; “PR8”)-induced lethality. Mice lacking Ptgs2, that encodes COX-2, a key proinflammatory M1 macrophage mediator, are more resistant. Blocking the receptor for COX-2-induced Prostaglandin E2 (PGE2) was also protective. Treatment with pioglitazone (PGZ), a PPARγ ligand, increased survival from PR8 infection, decreased M1 macrophage gene expression, and increased PPARγ mRNA in lungs. Conversely, conditional knockout mice expressing PPARγ-deficient macrophages were significantly more sensitive to PR8-induced lethality. These findings were extended in cotton rats: PGZ blunted lung inflammation and M1 cytokine gene expression after challenge with non-adapted human influenza. To study mechanisms by which PPARγ/RXR transcription factors induce canonical M2a genes, WT mouse macrophages were treated with IL-4 in the absence or presence of rosiglitazone (RGZ; PPARγ ligand), LG100754 (LG; RXR ligand), or both. IL-4 dose-dependently induced M2a genes Arg1, Mrc1, Chil3, and Retnla. Treatment of macrophages with IL-4 and RGZ and/or LG differentially affected induction of Arg1 and Mrc1 vs. Chil3 and Retnla gene expression. In PPARγ-deficient macrophages, IL-4 alone failed to induce Arg1 and Mrc1 gene expression; however, concurrent treatment with LG or RGZ + LG enhanced IL-4-induced Arg1 and Mrc1 expression, but to a lower level than in WT macrophages, findings confirmed in the murine alveolar macrophage cell line, MH-S. These findings support a model in which PPARγ/RXR heterodimers control IL-4-induced M2a differentiation, and suggest that PPARγ/RXR agonists should be considered as important tools for clinical intervention against influenza-induced ALI.

Secretion of related factors and AMPK/PGC-1 α signal pathway by alveolar macrophages in viral acute lung injury

“…the decrease of pulmonary surfactant is the main pathogenesis of VALI (11). Various pathogenic factors inside and outside the lung cause acute uncontrolled inflammatory reactions in lung tissue, resulting in alveolar capillary injury, increased permeability and pulmonary edema, which lead to progressive dyspnea and hypoxemia are the main pathophysiological changes of VALI (12). Alveolar enter the lung tissue, further aggravating the injury of lung tissue and promoting the development of patients with VALI (19).…”

Tumor-derived extracellular vesicles regulate macrophage polarization: role and therapeutic perspectives

“…IL-4 or IL-13 can effectively counteract inflammatory damage and promote tissue healing by stimulating macrophages to differentiate into M2a cells and release anti-inflammatory cytokines such as IL-1RA, IL-10, and transforming growth factor-beta (TGF-β) ( 40 , 41 ) via the co-receptor IL-4Rα. Arg1, Mrc1, Chil3, and Retnla are their primary markers of detection ( 42 ). When TLR or IL-1R agonists are exposed to the body, they produce M2b macrophages that release cytokines, IL-10, IL-1, etc., to exert immunomodulatory effects.…”

Significance of Pulmonary Endothelial Injury and the Role of Cyclooxygenase-2 and Prostanoid Signaling

“…Other viruses, such as RSV, HPIV-3 or H5N1, upregulate COX-2 in bronchial and bronchiolar epithelial cells and macrophages [184][185][186][187]. In a very recent paper, Gopalakrishnan showed that influenza infection induced COX-2 expression in inflammatory macrophages, which contributes significantly to influenza-induced lethality [188]. In contrast, poly(I:C), a viral PAMP that can be considered a synthetic analogue of double-stranded RNA present in, for example, reoviruses, which activates TLR-3, does not enhance COX-2 expression in mouse lung tissue.…”