Inflammation and immunity in IPF pathogenesis and treatment

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, and ultimately fatal, chronic interstitial lung disease characterized by enhanced extracellular matrix deposition. Repetitive alveolar epithelial injury triggers the early development of fibrosis. These injuries, in combination with dysregulated wound repair and fibroblast dysfunction, lead to ongoing tissue remodelling and fibrosis seen in end-stage pulmonary fibrosis. Although the exact etiology in IPF is unknown and probably diverse, all stages of fibrosis are accompanied by innate and adaptive immune responses. The role of inflammation as an important component in IPF etiology is controversial and sometimes seen as an epiphenomenon of fibrosis. This view is partly the result of negative multicenter trials of anti-inflammatory drugs for IPF treatment. However, new insights on the role of macrophages, the loss of Tcell and B-cell tolerance leading auto-immune responses in IPF, and the interaction of immune cells with (myo) fibroblasts have led to a slow change of this opinion. Clearly, more insight is needed to integrate basic immune mechanisms into translational research and finally new IPF therapies.In this concise review, we will focus on the role of our innate and adaptive immune system in the initiation and perpetuation of IPF pathobiology. Next, we will discuss how immune responses are influenced by current anti-fibrotic treatments, such as pirfenidone and nintedanib and end with an overview of recent and upcoming therapeutic trials that target and modulate our immune system in patients with IPF.

Nintedanib inhibits the development and progression of peritoneal fibrosis

“…We thus suggest that nintedanib has a powerful anti-inflammatory effect on peritoneal fibrosis. These results are consistent with its suppression of inflammation in animal models of IPF and renal fibrosis [9,25]. The protective effect of nintedanib from inflammation may be through its inhibition of multiple RTKs and Src, and subsequently, inactivation of their downstream signaling pathways, such as STAT3 and NF-κB.…”

Fibroblast‐specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease

“…7 It remains to be resolved as to what are the key sentinel cells in the lung: Immune and/or stromal, whether fibrosis and inflammation arise in series or in parallel and to what extent they are mutually dependent. [8][9][10] IL11 is a member of the IL6 family of cytokines and secreted by resident fibroblasts in response to profibrotic stimuli. IL11 binds to its specific receptor subunit Interleukin 11 receptor subunit alpha (IL11RA), which is highly expressed on stromal cells (eg, fibroblasts and smooth muscle cells) but not on immune cells, that then signals via the ubiquitously expressed gp130 receptor.…”

Fibroblast-specific IL11 signaling is required for lung fibrosis and inflammation

“…While fibroblasts have been implicated in inflammation-associated pathology of rheumatoid arthritis, colitis and IPF (7,(15)(16)(17)(18), it has not been shown conclusively whether the stroma is a modifier or primary driver of the inflammatory response. In the BLM model of lung fibrosis, we found that the deletion of IL11 signaling in fibroblasts alone is sufficient to protect mice from inflammation in the lung.…”

“…In recent years, a primary immune role for Th2 polarized T cells and the Th2 cytokine IL13 gained favor in IPF fibrogenesis but targeting IL13 in clinical trials was ineffective (5). It remains to be resolved as to what are the key sentinel cells in the lung, immune and/or stromal, and how fibrosis and inflammation arise temporally: in series, in parallel or independently (6,7). IL11 is a member of the IL6 family of cytokines that share the use of the GP130 receptor as part of their multimeric receptor-ligand complexes for signal transduction.…”