The Role of Macrophages in Connective Tissue Disease-Associated Interstitial Lung Disease: Focusing on Molecular Mechanisms and Potential Treatment Strategies

Abstract

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a severe manifestation of CTD that leads to significant morbidity and mortality. Clinically, ILD can occur in diverse CTDs. Pathologically, CTD-ILD is characterized by various histologic patterns, such as nonspecific interstitial pneumonia, organizing pneumonia, and usual interstitial pneumonia. Abnormal immune system responses have traditionally been instrumental in its pathophysiology, and various changes in immune cells have been described, especially in macrophages. This article first briefly overviews the epidemiology, clinical characteristics, impacts, and histopathologic changes associated with CTD-ILD. Next, it summarizes the roles of various signaling pathways in macrophages or products of macrophages in ILD, helped by insights gained from animal models. In the following sections, this review returns to studies of macrophages in CTD-ILD in humans for an overall picture of the current understanding. Finally, we direct attention to potential therapies targeting macrophages in CTD-ILD in investigation or in clinical trials, as well as the future directions regarding macrophages in the context of CTD-ILD. Although the field of macrophages in CTD-ILD is still in its infancy, several lines of evidence suggest the potential of this area.

CD163+ macrophage density in perimysial connective tissue associated with prognosis in IMNM

“…Immunoinflammation can lead to damage by activating nuclear factor κB (NFκB) signaling and increase the production of pro‐inflammatory cytokines such as IL‐1, IL‐6, and TNF‐α. 34 , 35 M2‐type macrophages that are imbalanced produce CCL18, which can lead to excessive tissue repair. This, in turn, promotes fibroblast proliferation and collagen deposition.…”

“…This, in turn, promotes fibroblast proliferation and collagen deposition. 35 Therapies that target macrophages can be classified as those that target macrophage receptors, such as blocking the “eat me” signal from CD47, or those that indirectly target cytokines secreted by or acting on macrophages. 36 In addition, as CD163+ macrophages are upregulated in inflammation, the CD163 receptor can be targeted via antibody‐drug coupling resulting in triggering endocytosis and release of the drug to fulfill its function.…”

The Lung in Rheumatoid Arthritis—Friend or Enemy?

“…The appearance of fibrosis occurs through three mechanisms. First, is the reduction of PAD2 in fibroblasts and the reduction of collagen deposits in the lungs; secondly, macrophages secrete high levels of IL-6, which determine the proliferation of T cells; the third stage involves high levels of TNF-α produced by macrophages that lead to inflammation and fibrosis in the lungs [ 129 ]. Two types of macrophages are defined regarding inflammation and immune modulation: M1 (classical or proinflammatory macrophage) and M2 (alternatively activated) [ 68 ].…”

“…Macrophage autoimmune–complement–interferon cascade genes are modified in RA-ILD and can have a profibrotic inflammatory response in the lungs. TNF-α leads to an inflammatory phase dominated by cell infiltration, followed by the fibrotic phase characterized by the irreversible deposition of collagen fibers in the pulmonary parenchyma [ 129 , 132 ].…”