Immunological Priming Requires Regulatory T Cells and IL-10–Producing Macrophages To Accelerate Resolution from Severe Lung Inflammation

Abstract

Overwhelming lung inflammation frequently occurs following exposure to both direct infectious and non-infectious agents, and is a leading cause of mortality world-wide. In that context, immunomodulatory strategies may be utilized to limit severity of impending organ damage. We sought to determine whether priming the lung by activating the immune system, or immunological priming, could accelerate resolution of severe lung inflammation. We assessed the importance of alveolar macrophages, regulatory T cells, and their potential interaction during immunological priming. We demonstrate that oropharyngeal delivery of low-dose lipopolysaccharide can immunologically prime the lung to augment alveolar macrophage production of interleukin-10 and enhance resolution of lung inflammation induced by a lethal dose of lipopolysaccharide or by pseudomonas bacterial pneumonia. Interleukin-10 deficient mice did not achieve priming and were unable to accelerate lung injury resolution. Depletion of lung macrophages or regulatory T cells during the priming response completely abrogated the positive effect of immunological priming on resolution of lung inflammation and significantly reduced alveolar macrophage interleukin-10 production. Finally, we demonstrated that oropharyngeal delivery of synthetic CpG-oligonucleotides elicited minimal lung inflammation compared to low-dose lipopolysaccharide, but nonetheless primed the lung to accelerate resolution of lung injury following subsequent lethal lipopolysaccharide exposure. Immunological priming is a viable immunomodulatory strategy used to enhance resolution in an experimental acute lung injury model with the potential for therapeutic benefit against a wide array of injurious exposures.

Phospholipase D isoforms differentially regulate leukocyte responses to acute lung injury

“…Interactions between these macrophage subtypes and neutrophils, indicators of ongoing efferocytosis, were also increased in Pld2‐ deficient mice. These macrophage subtypes participate in efferocytosis of apoptotic neutrophils for resolution of ALI, and release protective cytokines such as IL‐1ra, and IL‐10 . In addition, PLD2 gene knockdown was associated with increased human macrophage transmigration and phagocytosis by cells of proresolving M2 phenotype .…”

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation

“…69 Moreover, they have been shown to limit fibroproliferation and augment alveolar epithelial repair. 70,71 Given their limited numbers, Tregs have been shown to become highly proliferative after lung inflammation and are a key feature in controlling exuberant immune responses. 65,72 Ongoing clinical trials are evaluating the role of Tregs in solid-organ transplantation.…”

Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

“…Following intrapulmonary challenges with either LPS or K. pneumoniae , exudate macrophages are sources of IL-1RA, without which lung injury is exacerbated (126). And in a model in which exposures to low doses of LPS protect mice from subsequent and otherwise lethal doses of LPS or P. aeruginosa , IL-10 is the protective factor and derived from recruited monocyte macrophages (127). Finally, the bone marrow–derived mesenchymal stem cell can be a source of cell-mediated tissue resilience and represents a promising therapeutic strategy.…”