Secretory immunoglobulin A induces human lung fibroblasts to produce inflammatory cytokines and undergo activation

Abstract

Summary Immunoglobulin (Ig)A is the most abundant immunoglobulin in humans, and in the airway mucosa secretory IgA (sIgA) plays a pivotal role in first‐line defense against invading pathogens and antigens. IgA has been reported to also have pathogenic effects, including possible worsening of the prognosis of idiopathic pulmonary fibrosis (IPF). However, the precise effects of IgA on lung fibroblasts remain unclear, and we aimed to elucidate how IgA activates human lung fibroblasts. We found that sIgA, but not monomeric IgA (mIgA), induced interleukin (IL)‐6, IL‐8, monocyte chemoattractant protein (MCP)‐1 and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) production by normal human lung fibroblasts (NHLFs) at both the protein and mRNA levels. sIgA also promoted proliferation of NHLFs and collagen gel contraction comparable to with transforming growth factor (TGF)‐β, which is involved in fibrogenesis in IPF. Also, Western blot analysis and real‐time quantitative polymerase chain reaction (PCR) revealed that sIgA enhanced production of α‐smooth muscle actin (α‐SMA) and collagen type I (Col I) by NHLFs. Flow cytometry showed that NHLFs bound sIgA, and among the known IgA receptors, NHLFs significantly expressed CD71 (transferrin receptor). Transfection of siRNA targeting CD71 partially but significantly suppressed cytokine production by NHLFs co‐cultured with sIgA. Our findings suggest that sIgA may promote human lung inflammation and fibrosis by enhancing production of inflammatory or fibrogenic cytokines as well as extracellular matrix, inducing fibroblast differentiation into myofibroblasts and promoting human lung fibroblast proliferation. sIgA’s enhancement of cytokine production may be due partially to its binding to CD71 or the secretory component.

Secretory IgA accumulated in the airspaces of idiopathic pulmonary fibrosis and promoted VEGF, TGF-β and IL-8 production by A549 cells

“…Interestingly, serum IgA1 from patients with IgA nephropathy was reported to induce TGF‐β synthesis via the renin–angiotensin system in human mesangial cells . In line with this, our previous study showed that SIgA induces inflammatory cytokine production and collagen synthesis by human lung fibroblasts . In our present study, using alveolar epithelial cells, we show for the first time that high‐dose SIgA can induce production of two profibrotic cytokines, VEGF and TGF‐β.…”

Exhaled Biomarkers in Idiopathic Pulmonary Fibrosis—A Six-Month Follow-up Study in Patients Treated with Pirfenidone

“…Therefore, we believe that cytokine level measurements in serum, BALF and sputum should not be extrapolated to EBC in patients with IPF. Although IL-6, -8, -15, VEGF and TNF-α were shown to contribute to the pathogenesis of IPF [7,31,[34][35][36] their EBC levels in our study were either below the detection limit (IL-15 and TNFα) or did not differ significantly between patients with IPF and controls (IL-6, VEGF-A).…”

Is Cross-Reactive Immunity Triggering COVID-19 Immunopathogenesis?

“…Serum IgA may also contribute to immunopathology as suggested by its association with disease severity ( 12 , 19 , 20 ). sIgA are able to induce interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1 and granulocyte–macrophage colony stimulating factor (GM-CSF) production by normal human lung fibroblasts ( 45 ). On the other hand, serum IgA can also mediate anti-inflammatory effects in innate immune cells ( 46 ).…”