Interleukin-1β Modulation of the Mechanobiology of Primary Human Pulmonary Fibroblasts: Potential Implications in Lung Repair

Abstract

Pro-inflammatory cytokines like interleukin-1β (IL-1β) are upregulated during early responses to tissue damage and are expected to transiently compromise the mechanical microenvironment. Fibroblasts are key regulators of tissue mechanics in the lungs and other organs. However, the effects of IL-1β on fibroblast mechanics and functions remain unclear. Here we treated human pulmonary fibroblasts from control donors with IL-1β and used Atomic Force Microscopy to unveil that IL-1β significantly reduces the stiffness of fibroblasts concomitantly with a downregulation of filamentous actin (F-actin) and alpha-smooth muscle (α-SMA). Likewise, COL1A1 mRNA was reduced, whereas that of collagenases MMP1 and MMP2 were upregulated, favoring a reduction of type-I collagen. These mechanobiology changes were functionally associated with reduced proliferation and enhanced migration upon IL-1β stimulation, which could facilitate lung repair by drawing fibroblasts to sites of tissue damage. Our observations reveal that IL-1β may reduce local tissue rigidity by acting both intracellularly and extracellularly through the downregulation of fibroblast contractility and type I collagen deposition, respectively. These IL-1β-dependent mechanical effects may enhance lung repair further by locally increasing pulmonary tissue compliance to preserve normal lung distension and function. Moreover, our results support that IL-1β provides innate anti-fibrotic protection that may be relevant during the early stages of lung repair.

Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play

“…We have found that IL-1β downregulates col1a1 mRNA levels while increasing mRNA levels of mmp1 and mmp2 (the major collagenolytic enzymes), favoring a reduction in type I collagen in human pulmonary fibroblasts. These observations reveal that IL-1β may reduce local tissue rigidity and provide innate antifibrotic protection that could be important during the early stages of fibrotic processes and lung repair [24]. Other studies have demonstrated that the pan-RTK (receptor tyrosine kinase) inhibitor nintedanib can reduce the mRNA expression for mmp1, 4, 13, and 14 and pirfenidone is able to reduce mRNA expression for mmp3 and 13 [100].…”

Secretion of IL1 by Dedifferentiated Melanoma Cells Inhibits JAK1-STAT3–Driven Actomyosin Contractility of Lymph Node Fibroblastic Reticular Cells

“…Interestingly, FRC express high levels of IL1R1 and respond rapidly to systemic IL-1β stimulation in vivo (43). Furthermore, IL-1 inhibits the contractility of lung fibroblasts (52)(53)(54). The link between IL-1 and inhibition of the JAK1-STAT3 pathway needs further investigation, but it may involve activation of the p38 MAPK, as in synovial fibroblasts (55).…”

The Multiple Roles of CD147 in the Development and Progression of Oral Squamous Cell Carcinoma: An Overview

“…There, TGF-β1 is produced by both OSCC cells and CAFs [ 147 , 150 ]. In this framework, IL-1, IL-6, IL-8, and TNFα have been shown to stimulate the migration of specific subtypes of fibroblasts [ 151 , 152 , 153 , 154 , 155 , 156 , 157 ]. The same could occur for OSCCs, given the capability that inflammatory mediators or growth factors have to trigger CAFs locomotion [ 158 ].…”